WO2008051279A1 - Dispositif endovasculaire auto-expansible pour occlusion d'anévrismes - Google Patents

Dispositif endovasculaire auto-expansible pour occlusion d'anévrismes Download PDF

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Publication number
WO2008051279A1
WO2008051279A1 PCT/US2007/007320 US2007007320W WO2008051279A1 WO 2008051279 A1 WO2008051279 A1 WO 2008051279A1 US 2007007320 W US2007007320 W US 2007007320W WO 2008051279 A1 WO2008051279 A1 WO 2008051279A1
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WO
WIPO (PCT)
Prior art keywords
matrix
aneurysm
another embodiment
reticulated
elastomeric
Prior art date
Application number
PCT/US2007/007320
Other languages
English (en)
Inventor
Ivan Sepetka
Maria G. Aboytes
Ricardo Aboytes
Hong Thu Doan
Steven Hochberg
Peter Costantino
Craig F. Friedman
Arindam Datta
Original Assignee
Biomerix Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biomerix Corp filed Critical Biomerix Corp
Priority to CA002647321A priority Critical patent/CA2647321A1/fr
Priority to BRPI0709084-6A priority patent/BRPI0709084A2/pt
Priority to JP2009501592A priority patent/JP2009530042A/ja
Priority to EP07835714A priority patent/EP1998717A1/fr
Priority to US12/294,210 priority patent/US20090318941A1/en
Priority to AU2007309715A priority patent/AU2007309715A1/en
Publication of WO2008051279A1 publication Critical patent/WO2008051279A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
    • A61B17/12109—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel
    • A61B17/12113—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel within an aneurysm
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
    • A61B17/12168—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device having a mesh structure
    • A61B17/12172—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device having a mesh structure having a pre-set deployed three-dimensional shape
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
    • A61B17/12181—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00526—Methods of manufacturing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00867—Material properties shape memory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00893—Material properties pharmaceutically effective
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B2017/1205—Introduction devices
    • A61B2017/12054—Details concerning the detachment of the occluding device from the introduction device
    • A61B2017/12095—Threaded connection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39—Markers, e.g. radio-opaque or breast lesions markers

Definitions

  • the present invention provides an apparatus for aneurysm repair that includes a self-expandable frame and a physiologically compatible, resiliently compressible, elastomeric reticulated matrix.
  • Embodiments of the present invention provide systems and methods for treating aneurysms.
  • One embodiment of a system according to the present invention includes an apparatus for aneurysm repair having a self-expandable frame and a physiologically compatible, resiliently compressible, elastomeric reticulated matrix and a delivery device.
  • An embodiment of a method of treating an aneurysm includes the steps of: (a) providing an apparatus for aneurysm repair that includes a self-expandable frame and a physiologically compatible, resiliently compressible, elastomeric reticulated matrix, inserted into a lumen of a delivery device; the delivery device having a proximal end and a distal end, the distal end having a distal tip; (b) advancing the distal tip of the delivery device into an opening in an aneurysm having an interior sac; (c) advancing the apparatus through the lumen into the opening; and (d) withdrawing the delivery device, whereby the apparatus expands into the sac and covers the opening.
  • the method includes a step of sizing the aneurysm in order to provide or select an apparatus for aneurysm repair according to the present invention with the best fit to the aneurysm to be addressed.
  • Sizing of the aneurysm includes assessing the size of the aneurysm sac and/or the size of the aneurysm opening to determine a suitable size and configuration of the retention member or members, and the size and geometry of the frame of the aneurysm repair apparatus to be used.
  • a suitable size of frame of the apparatus is a size, which when fully expanded, is slightly smaller in each dimension than the equivalent dimension of the aneurysm sac, and thus fits snuggly into the aneurysm sac. Because the neck of the aneursym is in general smaller than the diameter of the aneurysm sac, the frame of the apparatus is secured and resists expulsion from the aneurysm.
  • the size of the neck or opening of the can be determined to aid in selection of an appropriately sized elastomeric matrix to cover or block the aneurysm opening.
  • the elastomeric matrix of the apparatus substantially seals the opening of the aneurysm.
  • the elastomeric matrix of the apparatus completely closes the opening of the aneurysm.
  • the present invention in one embodiment of another of its aspects, provides an apparatus for aneurysm repair, wherein the apparatus includes a self-expandable frame and a physiologically compatible, resiliently compressible, elastomeric reticulated matrix, wherein the apparatus radially and/or circumferentially conforms to the aneurysm, thereby facilitating sealing of the aneurysm.
  • the present invention further provides a method for treating an aneurysm having an aneurysm wall, with an apparatus comprising a body having a proximal cylindrical portion and a distal portion, wherein the apparatus comprises a self-expandable frame and a physiologically compatible, resiliently compressible, elastomeric reticulated matrix.
  • the method comprises the steps of: (a) providing the apparatus inserted into the lumen of a delivery device; (b) advancing the distal tip of the delivery device into the aneurysm; (c) advancing the apparatus from the delivery device to the aneurysm; (d) positioning the apparatus in the aneurysm; and (e) permitting the frame to expand into a fully expanded shape, or to expand until limited by the aneurysm wall.
  • the present invention also provides an apparatus for securing a medical implant directed to aneurysm repair, wherein the apparatus includes: a retention member coupled to the implant and adapted for positioning in an aneurysm in a vascular tissue, the retention member comprising an expandable radial component for retaining the implant in the aneurysm.
  • Figure 1 Spherical shape memory frame (1) arranged as spokes attached at each end to a nut and with a thin layer of matrix implant material attached to the frame as an external jacket.
  • FIG. 2 Spherical shape memory frame (2) as in (A), or metallic coils (3) with only a partial covering comprised of a spherical segment of matrix implant material (4).
  • Radiopaque markers (6) are attached to the arms for detection during delivery and deployment.
  • Figure 4 Coaxial delivery system with delivery guide wire (1), and external sheath (5) to provide support for internal sheath, having soft tip section with the lead-screw (2).
  • nitinol memory coil (8) is attached to nitinol memory coil (8) and folded and/or stretched for delivery.
  • Figure 5 Coaxial delivery system after delivery: Stretched Nitinol arms (10) of the frame with radial shape memory. Lead-screw section (7) of the internal delivery sheath.
  • Nitinol memory coil (8) stretched during delivery and is relaxed after detachment.
  • Figure 6 Expanded spherical shape memory frame after delivery and release from coaxial delivery system. Nitinol shape memory frame arms (10) radially expanded according to its retained shape memory. DETAILED DESCRIPTION OF THE INVENTION
  • the self-expandable apparatus of the invention may be constructed from any physiologically compatible matrix, attached to a self-expandable frame for delivery into the lumen of an aneurysm.
  • the matrix can be any physiologically compatible matrix, such as for instance and without limitation, the Biomerix matrix described in U.S. Serial No. 10/998,357 filed November 26, 2004.
  • the self-expandable frame can be constructed of any self-expandable material, such as a metallic frame, constructed from for instance, Nitinol wire.
  • the physiologically compatible matrix can be attached to the self-expandable frame of the self-expandable apparatus of the invention by any suitable method well known to those of skill in the art.
  • the matrix can be sutured to the frame with a biocompatible suture material.
  • the matrix can be glued to the frame.
  • the matrix can be heat-bonded to the frame, where the frame has been pre-coated with a suitable heat-activated polymer or adhesive.
  • the self-expandable apparatus of the invention can be constructed to conform to different shapes and sizes to accommodate a range of aneurysm sizes and shapes, with the goal of achieving a fit conforming to the wall of the aneurysm.
  • the self-expandable apparatus can seal the lumen of the aneurysm and thereby isolate it from the vasculature.
  • Platinum bodies of a size necessary for detection can also be incorporated into or onto the self-expandable frame to provide radiopacity for ease of following deployment of the apparatus and to aid in accurate placement within a target aneurysm.
  • the aneurysm repair apparatus of the invention includes a self-expandable frame and a physiologically compatible, resiliently compressible, elastomeric reticulated matrix.
  • the elastomeric matrix is a suitable substrate for tissue regeneration.
  • the resiliently compressible, elastomeric matrix can be biodurable.
  • the resiliently compressible, elastomeric matrix can be resorbable.
  • the reticulated elastomeric matrix is configured to permit cellular ingrowth and proliferation into the elastomeric matrix.
  • the elastomeric matrix is hydrophobic.
  • the elastomeric matrix includes an elastomer polymer selected from the group consisting of polycarbonate polyurethanes, polyester polyurethanes, polyether polyurethanes, polysiloxane polyurethanes, polyurethanes with mixed soft segments, polycarbonates, polyesters, polyethers, polysiloxanes, polyurethanes.
  • the elastomeric matrix can include a mixture of two or more of the above polymers.
  • the elastomeric matrix is reticulated and endoporously coated with a coating material that enhances cellular ingrowth and proliferation, m one example of the above embodiment, the coating material includes a coating, which can be a foamed coating, of a biodegradable material such as for instance, collagen, fibronectin, elastin, hyaluronic acid or a mixture of any of the foregoing biodegradable materials.
  • a coating which can be a foamed coating, of a biodegradable material such as for instance, collagen, fibronectin, elastin, hyaluronic acid or a mixture of any of the foregoing biodegradable materials.
  • the self-expandable aneurysm-sealing apparatus of the invention can be used alone as a single device to seal the neck of the aneurysm, or in combination with an embolic device, such as for instance, a matrix implant such as a Biomerix matrix, as described in U.S. Serial No. 10/998,357 filed November 26, 2004, and/or one or more embolic coils, to fill the lumen of the aneurysm.
  • an embolic device such as for instance, a matrix implant such as a Biomerix matrix, as described in U.S. Serial No. 10/998,357 filed November 26, 2004, and/or one or more embolic coils, to fill the lumen of the aneurysm.
  • the self- expanding apparatus of the invention can be deployed first to seal the aneurysm neck, followed by delivery of embolic device, or devices to fill the interior aneurysm sac, and thereby stabilize the repair of the aneurysm.
  • One or more embolic devices can be delivered by the same delivery micro-catheter used to deliver the aneurysm sealing apparatus.
  • the embolic device or devices can be delivered by the same microcatheter through the threaded opening of the nut (described below) attached to the matrix of the apparatus of the present invention that substantially seals the opening at the neck of the aneurysm.
  • Insertion of one or more coils, or matrix implants into the lumen of the sealed aneurysm offers the advantage of providing a scaffold to support contiguous tissue growth inside the aneurysm sac.
  • the self-expanding apparatus of the invention can also serve as a "neck protection" device, by expanding until confined by the aneurysm walls and extending beyond the aneurysm neck inside the aneurysm sac, preventing unwarranted migration of any filler (such as coils and/or matrix etc.) out of the aneurysm neck into the artery to which it is connected.
  • occlusion or sealing of the aneurysm by the apparatus of the present invention occurs first as the 'patch' formed by the resiliently compressible, elastomeric reticulated matrix of the expanded apparatus acts as a mechanical barrier which reduces the flow of blood from the parent vessel into and out of the aneurysm sac.
  • the reticulated matrix acts as a thrombotic patch and the stagnation of flow initiates the thrombotic response characterized by formation of a platlet-fibrin clot. This stage is followed by organization of the clot and finally, in the last stage of the healing response, resorption and resolution of the clot into fibrovascular tissue.
  • the apparatus of the invention for aneurysm repair includes a self-expandable frame and a physiologically compatible, resiliently compressible, elastomeric reticulated matrix, wherein the apparatus radially and/or circumferentially conforms to the aneurysm walls, thereby facilitating sealing of the aneurysm.
  • the self-expandable apparatus of the invention permits total reconstruction of the parental artery by delivering a patch of the physiologically compatible matrix across the neck of the aneurysm, thereby providing a tissue scaffold to promote endothelial growth.
  • the invention provides a self-expandable apparatus for securing a medical implant directed to aneurysm repair, wherein the apparatus includes: a retention member coupled to the implant and adapted for positioning in an aneurysm in a vascular tissue, and wherein the retention member includes an expandable radial component for retaining the implant in the aneurysm.
  • the retention member resists an expulsive force.
  • the retention member of the self-expandable apparatus is integral to the implant.
  • the radial component comprises two or more at least partially radial members.
  • the invention provides an implant, for use in treating a defect such as an aneurysm in a vascular tissue, that includes a material having a . composition and structure adapted for application to the defect and for biointegration into the vascular tissue when applied to the defect.
  • the application to the defect in the vascular tissue can be insertion into the defect.
  • the structure includes a scaffold, which can be a reticulated structure.
  • the reticulated structure is resiliently compressible.
  • the resiliently compressible reticulated structure can include an elastomeric material.
  • the elastomeric material can be a biodurable material, such as for instance, microporous ePTFE (expanded polytetrafluoroethylene).
  • the elastomeric material can be a biosorbable material.
  • the bioabsorbable materials for use as the elastomeric matrix material of the apparatus of the invention can be any bioabsorbable materials, such as for instance, but not limited to polyglycolic acid-polylactic acid (PGA/PLA) copolymers.
  • PGA/PLA polyglycolic acid-polylactic acid
  • Other suitable bioabsorbable materials can be solids, gels or water absorbing hydrogels with different bioresorption rates.
  • the implant in another particular example of the implant of the invention, includes a self-expanding retention member which when inserted into the defect, is of a size and dimensions to fit the defect.
  • the retention member expands to meet the walls of the aneurysm sac and thereby at least partially resist expulsion from the defect.
  • the retention member has a radial component.
  • the structure of the implant of the invention comprises interconnected networks of voids and/or pores encouraging cellular ingrowth of vascular tissue.
  • Figure 1 shows a spherical shape memory Nitinol frame (1), with a thin layer of implant material attached to the frame as a external jacket by surgical sutures to create a delicate self-expanding hollow structure.
  • the jacketted Nitinol sphere can be folded or stretched and loaded into a flexible tube, to allow the delivery through a catheter or over a guide wire. Once delivered to targeted site such as aneurysm or blood vessel, the spherical structure re-expands and is detached using controlled delivery system.
  • Figure 2 illustrates an implant using the same expandable frame with a spherical segment of matrix implant material (4) attached to provide a lower profile for delivery.
  • the self- expandable spherical frame is constructed using bare Nitinol wire arms (2), or Platinum coils (3).
  • Nitinol arms can be also constructed from different gauges of wires to provide different radial expansive force.
  • Figure 3 Shows another design variation in which the complex memory shape self-expandable spherical structure has an elliptically shaped implant patch of matrix material.
  • Complex memory shape can be used to provide optimal stability of the patch, especially in aneurysms with different sizes and shapes. Platinum markers attached to the arms can also be used to provide radiopacity during delivery and deployment.
  • the elliptical segment of matrix material can be selected to fit and cover different anatomies of aneurysm neck presented by individual patients.
  • the self-expandable apparatus of the invention can be delivered to the aneurysm site using a controlled detachment system.
  • the controlled delivery and detachment system can be a coaxial delivery and detachment system.
  • the apparatus of the invention for aneurysm repair that includes a self-expandable frame and a physiologically compatible, resiliently compressible, elastomeric reticulated matrix can be folded and/or stretched on a guide-wire or on an internal sheath (that may harbor a guidewire), in order to attain a cross section narrow enough to be preloaded into a second sheath, the external sheath for use as a delivery catheter.
  • the physiologically compatible, resiliently compressible, elastomeric reticulated matrix can be of any thickness that retains sufficient flexibility to be folded and/or stretched to a collapsed form for loading onto a guidewire or inner sheath of a delivery microcatheter provided the collapsed apparatus has a sufficiently narrow profile to be threaded through the vasculature to the site of the aneurysm.
  • the thickness of the physiologically compatible, resiliently compressible, elastomeric reticulated matrix is in a range from about 100 um to about 100m um (1 mm) when fully relaxed and expanded.
  • matrix is from about 200 um to about 800 um thick when fully relaxed and expanded.
  • the matrix is from about 400 um to about 600 um (1 mm) thick when fully relaxed and expanded.
  • the porosity of the physiologically compatible, resiliently compressible, elastomeric reticulated matrix can be selected to permit cellular ingrowth.
  • the average major dimension of the pores of the matrix can be optimized to encourage cellular ingrowth.
  • the pores have an average major dimension in a range from about 50 um to about 300 um.
  • the pores have an average major dimension of from about 100 um to about 250 um.
  • the pores have an average major dimension of from about 150 um to about 200 um.
  • the size of the delivery microcatheter ranges from about 0.018 inch to about 0.040 inch outside diameter (OD).
  • OD outside diameter
  • the OD of the delivery microcatheter can be 2 French (i.e. 0.026 inch/0.67mm) or 3 French (i.e. 0.039 inch/1.0 mm).
  • the inside diameter of the delivery microcatheter ranges from about 0.014 inch to about 0.021 inch).
  • the self-expandable apparatus of the invention can be designed to conform to a variety of sizes and shapes or geometries.
  • the self-expandable aneurysm repair apparatus of the invention when fully expanded, adopts a predetermined size and shape according to the shape memory of the metallic wire or other shape memory composition of the frame of the apparatus.
  • the apparatus when fully expanded can be any size from about 2 mm to about 20 mm, and can be any shape suited to fit a particular aneurysm sac.
  • the fully expanded apparatus can be spherical, elliptical, cylindrical or conical in shape.
  • the self-expandable apparatus of the invention when in its collapsed form, i.e when folded and/or stretched to be accommodated in a delivery microcatheter, has an OD of from about 2 French (i.e. 0.026 inch/0.67 mm) to about 5 French (i.e. 0.065 inch/1.7 mm).
  • the collapsed apparatus even when loaded into a microcather, maintains a high degree of flexibility so that the delivery device can be easily navigated through the vasculature.
  • the collapsed apparatus can be loaded onto an internal sheath and the internal sheath carrying the collapsed apparatus can itself be loaded into an external sheath of a delivery catheter.
  • Suitable external sheaths for delivery of the self- expanding apparatus of the invention can have an OD from about 3 French to about 6 French, or from about 6 French to about 7 French.
  • the particular shape and dimensions of the self- expanding apparatus of the invention chosen to repair a particular aneurysm depend.on the size . of the aneurysm, which can be readily determined by the practitioner by standard tests and measurements using radiopaque dye to fill the aneurysm and aid in assessing its shape and dimensions.
  • Aneurysms are generally from about 2 mm to about 20 mm in the largest dimension; small aneurysms can be from about 2 mm to about 4 mm; medium sized aneurysms are generally from about 5 mm to about 9 mm in the largest dimension; and the largest aneurysms are generally from about 10 mm to about 20 mm in the largest dimension; although even larger aneurysms are not unknown.
  • Such "giant" aneurysms have been known to require up to 5 m of coils to fill.
  • the size of the self-expanding apparatus of the invention chosen to repair a particular aneurysm is chosen to be slightly smaller than the size of the aneurysm.
  • the longest dimension of the self-expanding apparatus is chosen to be slightly smaller than the longest dimension of the aneurysm and the shape of the apparatus is chosen to most nearly match the shape of the aneurysm.
  • the self-expanding apparatus of the invention can be from about 2 mm to about 20 mm in the longest dimension. In another embodiment, the self-expanding apparatus of the invention can be from about 4 mm to about 15 mm in the longest dimension. In still another embodiment, the self-expanding apparatus of the invention can be from about 5 mm to about 10 mm in the longest dimension. Alternatively, the self-expanding apparatus of the invention can be from about 6 mm to about 8 mm in the longest dimension. It is estimated that 80% of aneurysms are between about 3 mm and about 10 mm in the longest dimension.
  • the delivery device is constructed to allow for optimal flexibility to navigate tortuous neuro-vasculature system. In one embodiment this is achieved with a guidewire of decreasing diameter from the proximal end (the end manipulated by the practitioner) to the distal end that delivers the self-expandable apparatus of the invention into the lumen of the aneurysm.
  • the present invention also provides a system for treating an aneurysm, the system includes a self-expandable apparatus constructed from a physiologically compatible matrix, attached to self-expandable frame for delivery into the lumen of an aneurysm, and a delivery device.
  • the delivery device can be any suitable delivery device, such as for instance, a catheter or an endoscope-guided catheter, wherein the endoscope assists in navigation of the catheter to the site of deployment of the self-expandable apparatus of the invention for aneurysm repair.
  • FIG 4 shows a particular coaxial delivery system of the invention, constructed from a axial delivery guidewire (1), and an external delivery sheath (5) to provide support for internal sheath (9), having soft tip section (2) distally located to the fused lead-screw section (7).
  • the soft tip section (2) is to navigate the system over the guide wire into the aneurysm or other targeted vasculature according to standard techniques for positioning a micro-catheter.
  • the lead- screw (7) is to deliver and detach the implant having a nitinol memory coil (8).
  • the foam matrix (6) is attached via the memory arms (10) to threaded nuts (3) and (4) as a jacket over the memory coil.
  • Nuts(3) and (4) and memory coil (8) are step- wound as a single coil from the same strand of Nitinol wire. Nuts (3) and (4) have a smaller diameter and pitch adjusted to mesh with lead- screw (7) for delivery. Mid-coil (8) has a larger inside diameter to glide over the lead-screw when stretched during delivery, or when compressed during the detachment.
  • the lead-screw (7) is first screwed onto proximal nut (4) all the way to the proximal end of the lead-screw, while stretching the implant memory coil and the arms into a straight position and engaging the distal screw until the distal tip of the lead-screw is screwed into distal nut 3.
  • the implant is locked in the stretched position and can be sheathed in external delivery sheath (5) for snaking through the vasculature to position the implant in the aneurysm and release into the aneurysm sac.
  • a particular advantage of this system is the flexibility of the coil construction to provide good flexibility and tracking through the tortuous vascular system.
  • FIGS 5 and 6 show an implant detached from the delivery device.
  • External delivery sheath (5) is held still while torque is applied to internal sheath (9).
  • the torque is transmitted to advance lead-screw (7) proximally and the memory coil begins to compress into it's retained memory shape.
  • Pressure from arms (10) expands the implant into the desired spherical shape.
  • the position of the implant can be adjusted to the optimal position and detached by unthreading and releasing from nut (3) and then from nut (4). Detachment occurs when the distal tip of the lead-screw (7) is un-screwed from the proximal nut (4).
  • the distal tip of the internal sheath (2) cab then be pulled into external sheath (5) and the delivery device can be withdrawn.
  • the invention provides a high level of control during the detachment of the implant.
  • the partially expanded implant can be withdrawn back into the delivery device by reversing the process, i.e. by applying torque in the opposite direction to the direction of torque during the initial delivery attempt and collapsing the arms, rethreading the distal nut onto the distal tip of the lead-screw and withdrawing the implant back into the delivery device.
  • Such non-optimal placement of the implant may occur for instance if the distal nut has been unthreaded and released from the distal tip of the lead-screw and the implant has partially expanded, but is either not accurately placed or has migrated into the parental artery from the initial delivery site.
  • the invention further provides a method of treating an aneurysm, wherein the method includes the steps of: (a) providing self-expandable apparatus constructed from a physiologically compatible matrix, attached to self-expandable frame for delivery into the lumen of an aneurysm, the apparatus being inserted into a lumen of a delivery device, the delivery device having a proximal end and a distal end, the distal end having a distal tip; (b) advancing the distal tip of the delivery device into an opening in an aneurysm having an interior sac; (c) advancing the apparatus through the lumen into the opening; and (d) withdrawing the delivery device, whereby the apparatus expands into the sac and covers the opening.
  • the delivery device of the invention is a catheter.
  • the apparatus for aneurysm repair includes a radiopaque frame, or one or more radiopaque markers, or radiopaque retention members and deployment of the apparatus by the catheter can be assisted by visualization under fluoroscopy.
  • the invention also provides a method for treating an aneurysm having an aneurysm wall with an apparatus that includes a body having a proximal cylindrical portion and a distal portion, wherein the apparatus includes a self-expandable frame and a physiologically compatible, resiliently compressible, elastomeric reticulated matrix.
  • the method includes the steps of: (a) providing the apparatus inserted into the lumen of a delivery device; (b) advancing the distal tip of the delivery device into the aneurysm; (c) advancing the apparatus from the delivery device to the aneurysm; (d) positioning the apparatus in the aneurysm; and (e) permitting the frame to expand into a fully expanded shape, or to expand until further expansion is limited by the aneurysm wall.
  • porous implantable products aw known that are intended to encourage tissues invasion ' ⁇ vrv ⁇
  • no fc ⁇ own implantable device has been specifically designed or is available &r the specific objective of being compressed for a ddivery-desvice, c.g,, 0' ca&eter, endoscope ox syringe, delivery to a biological site, being capable of expanding to occupy m ⁇ remain in the biological site and being of a particular pore size such £hai it can become ingrown with tissue at that site to serve a useful therapeutic purpose.
  • M ⁇ y poro ⁇ .R ⁇ tly'COi ⁇ pressible materials ace produced frompolyuretiiane foams formed by blowing during the polymerization process.
  • Ia general such known 2s processes are unattractive -r ⁇ m the point of view of biodurability because undesirable materials that can produce adverse biological reactions are generated, for example carcinogcnS j cytotoxic and the like,
  • a number of polymers having varying degrees of biodurability ate known, but coxrancrciaUy available materials either lack the mechanical properties needed to provide 30 an implantable device that can be compressed for delivery-device delivery tod can resifiently expand in situ, at the htwadcd. biological site, or lack sr ⁇ fi ⁇ cicnt porosity to induce adequate cellular ingrowth and proliferation.
  • Patent No.6,165,193 disclose avascular anplant framed of a compressible foam hydrogel that lues a compressed configuration from whicn it is expansible into a configuration substantially confoiming to the shape and size of a vascular malfbnaatiou to be eanbolized. Greene's hydrogel lacks the mechanical properties to enable it to regain its size and shape in vivo ware it to be compressed for catheter, endoscope or syringe delivery.
  • Brady et al, k U.S. Patent No.6,177,522 (“Brady '522"), disclose implantable porous polycarbonate polyur ⁇ thaae products comprising a polycarbonate that is disclosed to be a random copolymer of alkyl carbonates. Brady '522's crosslinked polymer comprises urea and biuret groups, when urea is present and methane and allophsaaie groups, when urethaae is present.
  • Brady et aL inU.S. Patent Application. Publication No.2002/0072550 Al (“Brady '550”), disclose implantable porous polyur ⁇ thane products formed from a po ⁇ yether OT & polyeatboaate Kn ⁇ ar Jong enaii- dioL Brady '550 does aot broadly disclose a biostable porous polyether or polycarbonate polyuretnane implant having iaooyamuate linkages and a Yoid conteait in excess of 85%, The diol of Brady "550 is disclosed to be free of tertiary carbon licOfeag ⁇ s.
  • Brady '550's d ⁇ socyanat ⁇ is disclosed to be 4»4'-dipb,eny]methane diisocymate containing less than 3% 2,4'-diphenyIm ⁇ thane diisocyanate. Furthermore, the final foamed polyurethane product of Brady '550. contains isocyanurate linkages and is not reticulated.
  • Brady et aL in ⁇ .S. Patent Application Publication No.2002/0142413 Al ⁇ "Brady '413", disclose a, tissue engineering scaffold for cell, tissue or organ growth. or reconstruction, c ⁇ nsprismga ' solvontHSxtiacted, or purified, r ⁇ culatedpolyur ⁇ thane, eg. a. poly ⁇ thor or apolycarlKiaat ⁇ l ⁇ Viag a Mgh void content ai ⁇ surface area.
  • Certax ⁇ ⁇ nboditn ⁇ nts employ ab ⁇ wing agent duriog ir ⁇ lymerization for void creatior L
  • a TOTpimal amount of cell window opening is effected by a hand press or by crushing end solvent extraction is used to remove the resulting residue.
  • Brady '4X3 does not di$ck>$e arosilieatly-compiessible teticulated'product or a process to make it
  • Gilson ct aL in U.S. PatentNo.6,245,090 Bl (“Gilson "), disclose an open c € -tt fe « ⁇ » transcafliBter ot j clndmg implant with a porous outer surface having good hysteresis properties, i.e., which, whe ⁇ used in a vessel that is continually ewpanding and contracting, is capable of expanding ' and contracting faster than the vessel. Additionally, ⁇ ilsoa's open cell foam ⁇ s not reticulated.
  • MacGregoir inU-S. Patent No.4,459,252, discloses cardiovascular prosthetic devices or implants comprising a porous s ⁇ rfac ⁇ aad anctwoifc of interconnected interstitial pores below the surfiuse in fluid flow coinmuaication with the eur&ce pons.
  • Gunatillake et aL > in U.S. Patent No. 6 > 420»452 C'Ci-aatillake '452").
  • GunfltUXake et at,, ⁇ x U-S-PatcntNo.6,437,073 disclose a degradation-resistant a ⁇ icono- opntaining polyor ethane which is, furthefm ⁇ to, non-elastomeric.
  • CTiachuk 330'% disclose a composition for implantation delivery of a therapeutic agent which compiisos; a biocompatible block copolymer having an elastomerfc block, e.g., polyolofiii, and a the ⁇ noplastic block* e.g., styrene, and a therapeutic agent loaded into, the block copolymer.
  • the Knchuk "330 compositions may lack adequate mechanical properties to provide a compressible catheter ⁇ endoscope-, or syringe-intcoducible, res ⁇ ieat space-Ofipupyi ⁇ g porous element that can occupy a biological site and permit cellular ingrowth and proliferation into the occupied volume.
  • Roseribluth ⁇ t aL, iatl.$. Pater* Application Publication No.2003/014075 Al (“Rosenbluth”), disclose biomedical methods, roateri-ils, e.g., blood-absorbing, porous, expansible, super-strength, hydrogcls, and apparatus for deterring or preventing endoteaks following endovascular graft implantation. Sosenbluth does not disclose, e.g., polycarbonate polyuretbane foams. Additionally, Roscnblu ⁇ 's polymer foam is not reticulated.
  • D ⁇ reume et al U.S. Patent No.6,309,413, relates to e ⁇ doluminal grafts and discloses various methods of producing a 10-60 ⁇ m porous grafts, including eludo ⁇ of soluble particulates such, as salts, sugar and hydr ⁇ gels fiom polymers, and phase inversion.
  • Tuch i ⁇ .U.S. Patent-Sfo.5,820,917, discloses a blood-contacting medical device coated with a layer of water-soluble heparin, overlaid by a porous polymeric coating through which the heparin can elate.
  • the porous polymer coating is prepared by methods such as phase inversion precipitation onto a stent yielding a product with a pore size of about 0,5-10 ⁇ m. Dereume and Tuch disclose pore sizes that may he too small for effective cellular ingrowth and proliferation ofuacoated substrates.
  • the above references do not disclose, s.g., an implantable device that is entirely suitable for deHvery-device delivery, resilient recovery &om that delivery, and long-term Tcsidcnc ⁇ in a vascular malformation, with the therapeutic benefits, e.g., repair and regeneration, associated wifh q>propriateiy-sizediniBrW-m ⁇ cted pores.
  • the above references do not disclose, e.g., such a device containing polycarbonate rnoictics.
  • Th* foregoing description of b-vckgroimd sit may include insights, discoveries, understandings or disclosures, or associations together of disclosures, that were not known to the relevant art prior to the present invention but which were provided by tho invention. Some such contributions of the invention may have been specifically pointed oi ⁇ herein where ⁇ other 8 wh c ⁇ ntaTjutiq ⁇ context Merely because a document may have been citedhere, no admission is made that the field of the document, -which, may. be quite different from that of the invention, is analogous to the field or fields of the invention,
  • the present invention solves fbo problem of providing a biological implantable device suitable for de ⁇ iverjNdevice, e.g., cafljet ⁇ r, endoscope, arfhoscope, l ⁇ proscop, cystoBcope or syringe, delivery to and long-term residence in a vascular and other sites in a patient, for example a tnanvr ⁇ al.
  • the invention provides a Modura&le, reticulated, rsalieatly-comprossibb elastomeric implantable device.
  • the implantable device is biodcrablo for at least 29 days.
  • the implantable device is biodurat ⁇ e for at least 2 months.
  • the implantable device is biodurab ⁇ o for at leagt 6 months.
  • the implantable device is bi ⁇ durabl ⁇ for at least 12 months.
  • the implantable device is biodnrable for at least 24 months.
  • the implantable device is biodurable for at least S years.
  • the implantable device is biodutable lor longer than 5 years.
  • ⁇ c clastome ⁇ c matrices of this invention can be engineered or tailored over a wide range of performance by varying the starting materials and/or the processing conditions for different functional or therapeutic uses.
  • the elastomer ⁇ c matrix as it becomes encapsulated and ingrown with cells find/or tissue, can play a less important rote.
  • the encapsulated and ingrown elastomeric matrix occupies only a small amount of space, does not interfere with the function of the regcown cells and/or tissue, and nas no tendency to migrate.
  • the inventive implantable device is reticulated, i.e., comprises an interconnected network of pores, either by being fonned having a reticulated structure and/or undergoing a itticulation process. Itis provides fluid pc ⁇ n ⁇ abilitytbroughouti ⁇ «m ⁇ l83itable device and permits cellular ingro-vrfh. and proliferation into the interior oftho implantable device.
  • the reticulated etest ⁇ meric matrix has pores with an average diaaeter oi oflier largest tr-a ⁇ 'erse dimensioQ ofatleast about 150 ⁇ m.
  • the reticulated elast ⁇ mo ⁇ c matrix has poxes with an average diameter oi other largest transverse dimension of greater than 250 ⁇ m.
  • the reticulated elastomeric matrix has pores with an average diameter or other largest transverse dimension of from about 275 ⁇ m to about 900 ⁇ m.
  • an implantable device comprise a reticulated elastomeric matrix that is flexible and. r ⁇ siHent and can recover its shape and most of its size after compression.
  • the inventive implantable devices have a resilient compressibility that allows the implantable device to be compressed under ambient conditions, e.g., at 25 0 C, from a relaxed configuration to a first, compact configuration for in vivo delivery via a do ⁇ very-dcviw and to expand to a second, working
  • Th ⁇ present inventioa can. provide truly r ⁇ ttcwlatcsd, flexible, resilient, biodurable elastonwric ajatrix, suitable for long-term implantation, and having sufficient porosity to encourage cellular ingrowth and proH&r ⁇ tion, in vivo, Ih mothOT embodiment, tiie kvcntion ⁇ ro ⁇ id « a pr ⁇ cess for producing a bi ⁇ durable, flexible, tetieulated, resilie ⁇ tly-comprcssible elastomeric niatrix, suitable for implantation, into patients, the process comprising forming pores in a weU-characte ⁇ zed biodurable elastomer by a process free of undesirable residuals that does not substantially change the chemistry of the elastomer, to yield an etastomeric matrix having a reticulated structure that, when implanted in a pan ' &nt,'is
  • the mvcntion provides a process for producing an elastorn ⁇ rjc matrix compriswjg a polymeric raalerial having a reticulated structure, the process composing: a) fabricating a mold having surfaces defining a microstmctural configuration for the elaatomeric matrix; b) charging the mold with a flowabl « polymeric material; c) solidifying the polymeric material; and d) removing the mold to yield the elastomeric matrix,
  • for the clastom ⁇ rit matrix can be shaped, configured and dimensioned to define a self-supporting elaatomeric matrix.
  • the resultant elastomeric matrix has a reticulated structure.
  • the fabricated mold can, in one embodixamt, bo a sacrificial mold that is removed to yield the reticulated elastomeric matrix. Such removal can be effected, for example, by molting, dissolving or si&IirOTJg-away ⁇ ft sacrificial mold.
  • the substrate or sacrificial mold can comprise a plurality or multitude of solid or hollow heads or particles agglomerated, or interconnected, one -with another at multiple points on each particle in fhe manner of a network.
  • Inon ⁇ embod ⁇ n ⁇ Qt th ⁇ mold hgs a aignificWrt three-dimensional extent wi&m ⁇ tiplcparticles extending in each dimension.
  • the particles of the mold may be interconnected using beat and/or pressure, e.g., by altering or fUsing, by means of an adhesive or solvent treatment, or by the application of a icduced pressure.
  • the polymeric material SHs the interstices between the particles.
  • the particles comprise a material haying a relatively low melting point, for example, a hydrocarbon wax.
  • the particles comprise a material having water solubility, for example, an inorganic salt such as sodium chloride or calcium chloride, a sugai; each as sucrose, a starch, such as com, potato, wheat, tapioca, mature or lice starch, or mixtures thereof.
  • the polymeric material can comprise an elastomer.
  • the polymeric material can.
  • the polymeric material can comprise a solvent-soluble bioduiabl* elastomer whereby the fl ⁇ wat ⁇ polymeric xaatejM cm comprise a solution of me poljraer.
  • the solvent can then 1» .removed or allowed to ⁇ vap ⁇ ate to solidify the polymeric miSeiiaL Ia another embodiment, UM process ⁇ $ conducted to provide an elast ⁇ me ⁇ cinatrix configuration allowing cellular ingrowth and proliferation into the interior of the elastom ⁇ ic matrix and the ⁇ lastomeric matrix is implantable into a patient, as described her ⁇ HiL With ⁇ outbet-igbound oyany ⁇ aitiC ⁇ to1heo-y,hm ⁇ ngahigh void content and a high degree of reticulatioa. is thought to aHow 1h ⁇ implantable devices to be completely ingrown aad prolifcrat?d with cells including tissues such as fibrous tissues.
  • the invention provides a process for producing an elastomeric matrix har ⁇ g a reticulated structvtre, the process compriEing: a) coating a reticulated fbajji template with a flow ⁇ ble resistant material, optionally a thc ⁇ noplastic polymer or a wax; b) exposing a coated surface of flie foam template; c) removing the foam template to yield ft casting of the reticulated foam template; d) coating the casting with an elastomer in & flowable state to form an clastot ⁇ edo matrix; ⁇ ) exposing a $w&C£ of the casting; and f) removing the casting to yield a i ⁇ cuiate ⁇ poly ⁇ rethaneelastomerio matrix comprising the elastomer.
  • the invention provides a lyophilization process for
  • an elastor ⁇ eric matrix having a reticulated structure, fb,e process comprising: a) forming a solution comprising a solvent-soluble biodumble elastomer In a solvent; b) at least partially solidifying the solution to form a solid, optionally by copling S the solution; and c) removing the non-polymeric material, optioually by subliming the solvent from, the solid under reduced pressure, to provide an at least partially reticulated elastanieric matrix comprising the elastomer.
  • the invention provides a polymerization process for0 preparing a reticulated claatonwric matrix, the process comprising admixing: a) apolyol component, b) an isocyanate component, c) a blowing agent, d) optionally, a crosslinki ⁇ g agent, 5 e) optionally, a chain extender, f) optionally, at least one catalyst, g) optionally, a smractact, and h) optionally, a viscosity modifier; to provide a crosslinked elastoraerio matrix and reticulating the dastomeric matrix by a 0 reticulation process to provide the ictici ⁇ 3tcd ela3tomcdc matrix.
  • Tho ingredients arc present in quantities the elr ⁇ tomeric matrix fa prepared and under conditions to (i) provide a crosslinked reailicntly-compressiblo bioduxabl ⁇ elastomeric matrix,, (u) control fonxiati ⁇ n of biologically undesirable residues, and (iii) reticulate the foam by a reticulation process, to provide Hie reticulated elast ⁇ meric matrix.
  • the invmtior provides a lyophi ⁇ zatiou process for preparing a reticulated elastametic matrix comprising lyoptilizing & flowable polymeric material, IQ ano ⁇ ere ⁇ r ⁇ bodi-aeat, the polymeric materialco-i ⁇ riae3 a.5 ⁇ l «fioiiofa solvent-soluble biodurable elastomer in a solvent.
  • file flowable polymeric material is subjected to s lyopMlization process comprising solidifying the
  • a solution of a biod ⁇ able elastomer in a solvent is substantially, but not necessarily co-nptetely, solidified, then the solvent is sublimed fiom that material to provide an at least partially reticulated elastome ⁇ e matrix.
  • the temperature to which the solution is cooled is below the freezing temperature of th « solution. Jo. another embodiment, the temperature to which the solution is cooled is above the apparent glass transition temperature of the solid and below the freezing temperature of the solution.
  • the invention provides a process for preparing a reticulated composite elastomcric implantable device fox implantation into a patient, the process comprising surface coating or endppoiously coating a biodurable reticulated clastoojcric matrix with, a coating material selected to encourage cellular i ⁇ growth and proliferation.
  • the coating material can, for example, comprise a foamed coating of a biodegradable material, optionally, collagen, fibronectin, elastia, hyaforoaic acid scad mixtures thereof
  • the coating comprises a biodegradable polymer aadaa inorgan ⁇ c component.
  • the inv ⁇ ntioD provides a process for preparing a reticulated composite elastomeric implantable device useful for implantation into a patient, the process comprising surface coating or e ⁇ doporously coating or impregnating a reticulated b ⁇ o ⁇ urable elastomer.
  • Tbk coating or impregnating xnaisrM can, far example, comprise polygfycoHc acid ("FGA.”), polylactic acid (TLA”), polycaprolactic acid (TCL”), poly-p-dioxaaone C ⁇ JO"), PGA/PLA.
  • Another embodiment involves surface coating or sodacefiis ⁇ on, wherein, the porosity of the surface is altered,
  • tlie invention provides a method for treating an vascular malformation in a patient, such as an animal, the method comprising; a) compressing the herein-described inventive implantable device from a relaxed configuration to a first, compact configuration; b) delivering the compressed implantable device to the in vivo site of the vascular raatf ⁇ n ⁇ ition via a delivery-device; and c) allowing the implantable device to TuSiliently recover end expand to a second, working configuration at the in vivo site.
  • PigUTD 7 is a schematic view showing one possible morphology for a portion of t&e ⁇ crostruotur ⁇ of one embodiment of a porous biodnxable elastomeric product according to the invention
  • Figure 8 is a schematic block flow diagram of a process for preparing a porous oioduraWe ⁇ lastoraeric implantable device according to the invention
  • Figure 9 fe a schematic block flow diagram of a sacrificial molding process for preparing a reticulated b ⁇ odurabl ⁇ dastojneric implantable device according to the invention
  • Figure 10 is a schematic view of sn apparatus forperfo ⁇ niag the sacrificial rnolding process illustrated in figure 3;
  • Figure I l is a schematic blocfe flow diagram, wiSi acc ⁇ mpanyiag product sectional views, of a double lost wax process fbr preparing a reticulated biodurable elastomerio implantable device according to the invention;
  • Figure 12 is a scanning electron micrograph image of tae reticulated elastomeric implantable device prepared in Example 3.
  • Figure 13 is a histology elide of axeticulatcd implantable device prepared according to Example 3 following removal after 14 day implantation in the subcutaneous tissue of a Sprag ⁇ o-Daw ⁇ ey rat.
  • Certain embodiments of the invention comprise reticulated biodurable elastomer products, which are also compressible and exhibit resilience in their recovery, that have a
  • vascular malfo ⁇ natioa incl ⁇ de ⁇ but is not limited to aneurysms, art ⁇ rio venous malfqnctjoiis, arterial embolizations and other vascular abnormalities.
  • ⁇ oibodim ⁇ ⁇ ts involve reticulated bi ⁇ durable elastomer products for in vivo delivery via catheter, endoscope, orthoscope, lapxoscope, cystoscopy syringe or ofher suitable delivery-device and can be l ⁇ tisfactorily implanted or otherwise exposed to living tissue and fluids for extended periods of time, for example, at least 29 days.
  • implantable devices that can. be delivered to an in vivo patient site, for example a site in a human patient, that can, occupy that site for extended periods oftime without being harmful to the host Ih one embodiment; such implantable devices can also eventually become integrated, e.g. > ingrown "with tissue.
  • an implantable system which, e.g., can optionally reduce blood flow due to the pressure drop caused by additional resistance, optionally cause immediate thrombotic response leading to clot formation, and eventually lead to fibrosis, i.e., allow for and stimulate natural cellular ingrowth and proliferation into vascxdarinalfbt-natitma and the void space of implantable devices Itocated in vescular roalfo ⁇ atioHs, to stabilize and possibly seal off sucb features in a biologically sound, effective and lasting manner.
  • certain embodiments of the reticulated biodurat ⁇ e elastomeric proctofits of the invention comprise, or are largely, if not entirely, constituted by a higily permeable, reticulated matrix formed of a biodurable polymeric elastomer that is resiliently-conipieasible HO as to regem its shape after delivery to a biological site.
  • the elastomeric matrix is ch ⁇ x ⁇ CEtlly weU-dLaractenzed, In another
  • the elastom ⁇ rio matrix is physically well-cliaract-xized
  • the elastpmeric matrix is chemically and physically woll-ciiaiactwized.
  • Certain embodiment, of the invention can support cell growth and permit cellular ingrowth and proliferation in vivo and are izsott.1 as in vtvo biological implantable d ⁇ vices, for example for treatment of vasculature problems that may be used in vitro or in vivo to provide a substrate for cellular propagation.
  • the reticulated elastomeric matrix of the invention facilitates tissue ingrowth by providing a surface for c ⁇ ltalar attacihtnmt, migration, proliferation, and/or coating (e.g., collages) deposition
  • any type of tissue can grow into an implantable device comprising a reticulated elastomeric matrix: of the invention, including; by way of example, epithelial tissue (which includes, e.g., squamous, cuboidal and columnar epithelial tissue), co ⁇ nectivo tissue (which includes, eg., areolar tissue, dense regular and irregular tissue, reticular tissue, adipose tissue, cartilage sod tone), and amscle tissue (which includes, e.g., skeletal, smooth and cardiac muscle), or any combination thereof, e.g., fibrovasc ⁇ lar tissue, Ia -mother embodiment of &e invention, an implantable device composing a reticulated elast
  • the invention comprises an implantable device having sufficient resilient compressibility to be delivered by a "delivery-device", i.e. » a device with a chamber fbr containing an elastomeric implantable device while it is delivered to Hie desired site den released at the site, e.g., using a catheter, endoscope, orthoscope, laprosc ⁇ pft, cystoscope or syringe.
  • a delivery-device i.e. » a device with a chamber fbr containing an elastomeric implantable device while it is delivered to Hie desired site den released at the site, e.g., using a catheter, endoscope, orthoscope, laprosc ⁇ pft, cystoscope or syringe.
  • the thus-deliveied elastomeric implantable device substantially regains its shape after delivery to a biological site and hag adequate biodurability and tiocoi ⁇ patibility characteristics to bo suitable for long-term implantation.
  • the structure, morphology and properties of the elastomeric matrices of this invention can be engineered ox tailored over a wide range of performance by varying the starting materials and/or the processing conditions for different functional or therapeutic uses.
  • elaatora ⁇ c matrices of the invention have sufficient resilience to allow substantial recovery, e.g., to at least about 50% of the size of the relaxed configuration in at least one dimension, after being compressed for iatpha-tstion i ⁇ .
  • elastomeric matrices of the invention have sufficient resilience to allow recovery to at least about 60% of the size of the relaxed configuration in at least one dixneosion after being compressed for implantation, in the hux ⁇ a ⁇ body.
  • ⁇ lastomeric matrices of the invention have sufficient resilience to allow recovery te,at least about 90% of the size of the relaxed configuration in at least one d ⁇ en ⁇ on after being compressed for implantation Jn the human body.
  • biodwr ⁇ W describes elastomers and other products tfcat ate stable for extended periods of time in a biological environment. Such products should not exhibit significant symptoms of breakdown ox degradation, erosion or significant deterioration of mechanical properties relevant to their employment when, exposed to biological environments for periods of time commensurate with tho use of the implantable device.
  • the period of implantation may be weeks, months or years; the lifetime of a host product ⁇ which, the elastomeric products of the invention are incorporated, such as t graft or prosthetic; or the lifetime of a patient host to the elastomeric product, Inonecmbodimen ⁇ i.ied.c ⁇ irsdpe.iodofcxposureistobe understood to be at least about 29 days.
  • the desired period of exposure is to bo understood to be at least 29 days.
  • biodurable products of the invention are also biocompatible.
  • the terra "biocompatible" means that the product induces few, if aay, adverse biological reactions when implanted in a host patient Similar considerations applicable to "biodurable” also apply to the property of "biocompatibility*.
  • Aa intended biological environm « ⁇ t can be understood to in vivo, ⁇ .g., that of a patient host into which the product is implanted or to which the product is topically
  • EXHIBIT 1 applied, for example, a ⁇ aroma-ianhostsuch as a Is-nuio being or other primate, apot or ⁇ cnrts anJmat aUvcstoctorfbodanHQri, or a laboratory sai ⁇ All sucli uses are contemplated as being -within the scope of the invention.
  • a "patient" is an animal. Ja, one eraboiuroent, the animal is & bird, deluding but not limited to a chicken, turkey, duck, goose or quail, or amammal. In another embodiment, the animal is a ⁇ iwmmal.
  • the animal is a primate or ehranatt. In ffl ⁇ >thc ⁇ etobodm ⁇ ot, the animal is a human.
  • structural materials for the inventive porous elastomers are synthetic polymers, especially, but not exclusively, elastomeric polymers that ace resistant to biological degradation, for example polyca&onstc pofyurotha&es, polyether polywrethaacs, polysil ⁇ xanes and the like.
  • elastomers are g ⁇ t ⁇ lly hydrophobic but, pursuant to the invention, may be treated to have surfaces that are less hydrophobic ox somewhat hydrophilic. Jn. another embodiment, such elastomers may be produced with surfaces that an? less hydrophobic or somewhat hydroph ⁇ ic.
  • the “mactostmetra*” refers to the overall physical characteristics of an article or olgect formed of the biodwrabl ⁇ elastomeric product of the inversion- such as: the outer periphery s$ descilbed by the geometric limits of the article or object, ig ⁇ oring the pores oc voids; the "macrostructural surfece area” which references the outer surface areas as Uiowgh the pores were filled and ignores the surface areas within the pores; the “macrostructural volume” ox simply the "volume” occupied by the article or object which is fixe volume bounded tty the macrostructaral, or simply “macro” surface area; and the “bulk density” widchis the weight per unit volume of the article or object itself as ' distinct from the density of the structural material
  • the "rx ⁇ crostr ⁇ cturo” refers to the features of the interior structure of the biodurable elastomeric material fror ⁇ which the inventive products are constituted such as pore dimensions; pore outface area, being the total area, of Hie material surfaces in the pores; and the configuration of the struts and intersectiona that constitute the solid structure of certain embodiments of the iavontiv ⁇ elastoracdc product.
  • PSgur ⁇ 7 is a convenient way of illustrating some of the features and principles of the ⁇ crostructuxe of some embodiments of the inveotioiL
  • This %HB is not intended to be an idealized depiction of an embodiment of; nor is it a detafl ⁇ d rendering of a particular embodiment of the ⁇ lastometic products of the iav ⁇ ntion-
  • Other feat ⁇ res and principles of&o ⁇ icro-rtr ⁇ cture will be apparent fiom the present specification, or -will be apparent fiora one or more of Uw inventive processes for manufacturing prows elastomeric products that are described herein.
  • the microsiructure of the .Unstated porous b ⁇ odurable elastomeric malrix 100 which, may, inter alia, bo an individual element having a distinct shape or an extended, continuous or amorphous entity, comprises a reticulated solid phase I2 ⁇ fotmed of a suitable biodurabte elastomeric material and interspersed Ihercwithia, or defined thereby, a continuous interconnected void phase WO the latter being a principle feature of a reticulated structure.
  • the elastomeric material of winch elasto ⁇ wric matrix 100 is constituted may be a mixture or blend of multiple njaterials.
  • Ihe ⁇ lastommc material is a single synthetic polymeric elastomer s ⁇ rih as vrfll be described in more ' detail below.
  • Void phase MOwfll nsually be air- or gas-filled prior to use. I>ariag use, void phase 140will in many but r ⁇ t all cases become filled with liquid, for example, with biologioal fluids or body fluids.
  • Solid phase lS ⁇ ofdsstomeric matrix 1M> &sshown in Figure 7 - has an organic structure and comprises a multiplicity of relatively thin struts l ⁇ Othat extend between and interconnect a number of intersections ISO. Ihe intersections i so are substantial stmctural locations where three or more skats l ⁇ on ⁇ et one another. Four or five or more struts 160 may be seen to meet at an intersection i S Q or at a location, where two intexsection f i 180 cm be se ⁇ ntom ⁇ rgeinto one another, ⁇ a.
  • any given strut i ⁇ > ⁇ may extend ⁇ xwn an intersection 180 no any direction relative to other struts ">0fliat join at tbat int ⁇ issection ' s ⁇ Struts l6 ⁇ > and intersections iscjnay have g ⁇ naratty craved ahapea and define between them a
  • a small number of pence 2 ⁇ M may have a cell wall of structural material also called a “window” or “window pane” such as cell wsJl 220.
  • a cell wall of structural material also called a “window” or “window pane” such as cell wsJl 220.
  • Such cdl wallx? are undesirable to the extent that they ot ⁇ trcct the passage of Md and/or propagation and proliferation of tissues tough pores 200.
  • CeH walls 220 may, in one embodiment, be removed in a suitable process step, such as reticulation as discussed below.
  • solid phase 120 can be provided with a plurality of such fibrils (not shown), e.g., from about 1 to about 5 fibrils per strut 16 0 or intersection 18O.
  • fibrils- may be useful, for example, for the additional surface areathftyprovido.
  • ⁇ utfo projecting or protuberant structures may impede or restrict flow through pores 200.
  • Struts ⁇ 5O and intersections l8 ° can be considtsrcd to define the shape and oon-%utBiionofttepoi ⁇ 2 ⁇ w 1-iatmakeupvoidpb ⁇ i ⁇ (orv ⁇ ve « Many of pores 200, in ⁇ o far as they may be discretely identified, open into and communicate with at least two other pores 200. At intersect-one 1 ⁇ o. three or more pores 2 ⁇ x»tnay be considered to meet and intercommunicate. Ia certain embodiments, void phase 140 is continuous or substantially continuous throughout elastomeric matrix I Q O, meaning that there are few if any closed cell pores 200. Such closed cell pores 200 represent loss of useful volume azid may obstruct access of useful fluids to interior strut and intersection structures UW and 180
  • such dosed cell pores 2 «Uf present, comprise less than about 15% of the volume of eiastomeric matrix 100
  • such closed cell pores 20 «, if present, comprise less than about 5% of the volume of et ⁇ stomeric matrix ! ⁇ * ⁇ >• Jh
  • such closed cell pores 200 if present, comprise less than, about 2% of the volume of elagtomerie matrix io ⁇ .
  • the presence of dosed cell pores 200 can be noted by their influence in reducing the Volumetric flow tate of a fluid through elastomeric mafcrib.
  • eioo and/or as a reduction in cellular ingrowth, and proliferation into clastomeric matrix ioo.
  • k toother embodimeiit. ekstomedc IaEtIiS 1 ⁇ iS reticulated, lit another embodiment, eiastomeric matrix ioo is substantially r ⁇ tic ⁇ lst ⁇ d, Ia another embodiment, dastomOTcmatrix lw i8 Myreticd ⁇ ed.
  • elastomedc matrix ioo has many cell walls 220 removed.
  • solid phase 120 which maybe described as reticulated, comprises a continuous network of solid structures, such as struts 16 ° and intersections tso without any significant tc ⁇ ainatioos, isolated zones ox df ⁇ c ⁇ rjtiaufties, other than at the boundaries of the eiastomeric matrix, in which network a hypothetical line may be traced entirely through the material of solid phase 12 « from one point in the network to my other point in the network.
  • void phase 140 is also a continuous network of interstitial spaces, or mtercos ⁇ municating -Md passageways lor gases or liquids, which fluid passageways extend throughout and are defined by (or define) the structure of solid phase 120 of eiastomeric matrix ⁇ Oand open into ail its exterior surfaces.
  • solid phase 120 of eiastomeric matrix ⁇ Oand open into ail its exterior surfaces.
  • a hypothetical line may be traced entirely through void phase 140 from one point in the network to say other point in the network.
  • the microsteuctore of eiastomeric matrix * w is constructed to pemit or encourage cellular adhesion to the surfaces of solid phase i2O,neointmia formation thereon and ceQ ⁇ lar and tissue ingrowth and proliferation into pores 200of void phase 140 when eiastomeric matrix
  • such cellular ox tissue ingrowth sod proliferation which may for some purposes include fibrosis, can occur or be encouraged not just into exterior layers of pores 200. but into the deepest interior of and throughout elastomeric matrix i o ⁇ .
  • the inventive implantable device functions so that ingrown tissue ia kept vital, for example, by the prolonged presence of a supportive micarovasculatuie.
  • elastomeric matrix 100 is reticulated with open interconnected pores. Without being bound by any particular theory, this is thought to permit natural irrigation of the interior of elastomeric matrix lOOwith bodily fluids, eg., blood, even after a cellular population has become resident ia the interior ofelaatomcric matrix i° ⁇ so aa to sustain that population by supplying nutrients thereto and removing waste products therefrom.
  • elastomeric matrix 1 ⁇ is reticulated with open interconnected pores of a particular size range.
  • ⁇ t is intended that the various physical and chemical parameters of elastomeric matrix 100 including in particular the parameters to be described below, be selected to encourage cellular ing ⁇ ywtb. and proliferation according to the particular application for which an otastomeric matrix 100 is intended.
  • elastomeric matrix 100 that provide interior cellular irrigation will be fluid permeable and may also provide fluid access through and to the interior of the matrix for purposes other thsa cellular irrigation, for example, for eMon of phamiace ⁇ tica-ly*active agents, c,g» > a drug, or other biologically useful materials. Such materials may optionally be secured to the interior surfaces of olastonaerio matrix 10c.
  • gaseous phase l20 can be filled or contacted "with a deliverable treatment $9% for example, a sts ⁇ lant such as ozone or a wound h ⁇ &l& ⁇ t such as nitric oxide, provided that the m& ⁇ ost ⁇ ictural surfaces are sealed, for example by a bioabsorbable membrane to contain the gas witi ⁇ a the implanted product until the membrane erodes releasing the gas to provide a local therapeutic or
  • Usefi-1 ⁇ mbod ⁇ neot ⁇ of the iave ⁇ tioa include structures that ara somewhat randomized, as shown in Figure 1 where ⁇ w sht ⁇ s and mm of struts ⁇ o,irrt6i8ections 18 « and pores 2 ⁇ ⁇ * vary aab divisioniaUy, and more ordered stcuctums which also exhibit the described features of tfow ⁇ im ⁇ Qimdmt ⁇ structural c ⁇ E-pfcSity and high fluid permeability.
  • Such more ordered structures can be produced by the processes of the invc ⁇ ti ⁇ a as w ⁇ l be further described below.
  • the volume of void phase 14O is fiom about 70% to about WA of the volume of dastojtaerio matrix l ⁇ w - Xa another einbodf ⁇ ent, the volume of void phase wois from. abx>ut SO%to about9S% ofthevoliimoofela ⁇ ii-o ⁇ c-n ⁇ d3i ⁇ ioo. Jja aoothw ⁇ a ⁇ odiment, the volume of void phase t40 is from about 90% to about 9S% of th ⁇ volume of clasto- ⁇ riu matrix MW.
  • the "average diameter or other largest transverse d ⁇ ucnsiou 11 refers to the nutdber average diameter, for spherical oz substantially spherical pores, or to the number average largest transverse dimension, for
  • the average diameter or other largest taansverse dimension of pores 200 j s at least about 100 /an.
  • IQ another embodimcjitj t-j ⁇ w ⁇ rago -ttBii ⁇ etetoro& ⁇ rlwg ⁇ sttramve ⁇ w dimension ofpores 2 W is at least about 150 pHL Jh another eaabodBment,the average diameter or other largest transverse dimension of pores 200 is at least about 250 /cert.
  • tho average diameter or other largest transverse dirn ⁇ nsion of pores 200 is greater t ⁇ aa about 250 ⁇ m.
  • the average diameter or other largest transverse dimension, of pores 200 is at least about 275 ⁇ m.
  • the average diameter or other largest transverse dimension of pows 2o°is greater than about 275 ⁇ m, fa anoHwar embodiment, flw average diameter or other largest transverse ditaensioa of pores 2W is greater than 275 j ⁇ n.
  • the average diameter or other largest transveise dimension of pores 200 is at least about 300 paxu In.
  • the average diameter or otiose largest transverse d ⁇ n ⁇ nsio-i of pores 20 «is greater than, about 300 ⁇ ui.
  • the average diameter or other largest transverse dimension of pores 200 is greater than 300 ⁇ m.
  • the average diameter or other largest transverse dimension of pores 200 is not greater than about DOO ⁇ WL
  • the average diameter or other largest transverse dimension pfpores 2 ⁇ > is not greater that, about.850 ⁇ m. in. saother embodiment, the average diameter or other largest transverse dimension of pores 2410 Is not greater than about 800 ⁇ xn.
  • the average diameter or other largest transverse dimension of pores 2uo not greater than about €00 ⁇ m. J& another embodiment, the average diameter or other laxgest.transveise dimension of pores 200k not greater than about 500 ⁇ m.
  • the average diameter or other largest transverse dimension of poxes 200 is from about 150 ⁇ ax to about €00 ⁇ m.
  • the average diameter or other largest transverse dimension of pores 20 is fiom about 200 ⁇ & to about 500 /an.
  • the average diameter or other largest traasvctsc dimension of pores 2 ⁇ o is greater than about 250 ⁇ m. to about 900 ⁇ m, Jn another embodiment, the average diameter or other largest transverse dimension of paces 200 is greater than about 2S0 /tin to about 850 ⁇ m. Ta.
  • the average diameter or other largest transverse dimension of poxes 200 is from about 150 ⁇ ax to about €00 ⁇ m.
  • the average diameter or other largest transverse dimension of pores 20 is fiom about 200 ⁇ & to about 500 /an.
  • the average diameter or other largest traasvctsc dimension of pores 2 ⁇ o is greater than about 250 ⁇ m. to about 900 ⁇ m
  • the average diaractar or other largest transverse d ⁇ nc ⁇ si ⁇ ii of pores 200 is greater than about 250 jm to about 700 /m.
  • the average diameter or other largest transverse dira ⁇ nsio ⁇ of pores 20 ° is greater than about 250 ⁇ xa to about 600 ⁇ m.
  • the average diameter o ⁇ other largest transverse dimension of pores 200 is from about 275 im to about 900 ⁇ m.
  • the average diameter or other largest transverse dimension of pores 200 from about 275 ⁇ m to about 850 ⁇ m, 3 ⁇ another embodiment, ttw average diameter or other largest transverse dimension of pons 2( w is from about 27$ ⁇ m. to about SOO ⁇ m.
  • Ia a ⁇ o ⁇ jer etabodimcnt the average diameter or other largest transverse di ⁇ jca-don of pores 200 is from about 275 ⁇ m. to, about 700 /on.
  • R. mother ⁇ bodim ⁇ t the average diameter or otter largest transverse dimeosio ⁇ of pert* 200 is from about 275 ⁇ m to about COO ⁇ t&.
  • Pore size, pore size dietributiorj, ⁇ ur&ce srea > ga ⁇ pconeab&ty and liquid permeability can be measured by co ⁇ ve ⁇ &ujal methods known to those in the ait. Some measttfcmeqt methods are s-unmaii ⁇ d, e.g., by A. Jena and K.
  • Et ⁇ tome ⁇ cinab ⁇ i ⁇ H>c ⁇ be ⁇ eadflyf ⁇ Jt is a benefit of the invention, that elaat ⁇ meric mairix 100 is suitable for mass production from bulk stock by subdividing such bulk stock, e.g., by cutting! die punching, laser slicing, or compression molding. In one embodiment, subdividing the bulk stock can be done using a heated surface. It is a. fi ⁇ fhcr benefit of ⁇ o invention that the shape and configtttatioiiof elastomeric matrixlOOr ⁇ ay vary.wielely and ca ⁇ readily be adapted to desired anatomical tnorpflol ⁇ gi ⁇ s.
  • ekstome ⁇ c laatrix 100 can be either custoinized to apaxticular explication or patient or staadardizedfierioafls producuOa Howler, cconondc considerations iav ⁇ r ⁇ t ⁇ dsirdizaticrt-, ToGiia e ⁇ d, ⁇ lastoroenc matrix 100 can bo embodied in a kit composing elastomeric irapkntable
  • multiple, e.g. two, three or fotff, individual elastc ⁇ neric matrices »>o can be usod as aa implantable device system fot a single target biological site, being sized or shaped or both sized and shaped to fhnctio ⁇ cooperatiVrfyfcrtfeEtouyitofaiiindiYidttal target site.
  • tf ⁇ * t ⁇ t ⁇ i ⁇ p ⁇ m ⁇ mrmaimi of elast ⁇ wric matrix lOO may be as
  • Ia an alternative erabodimant, m elastoma ⁇ c matrix too having a spherical, cubical, t ⁇ trahedral, toroidal or other farm having no dimeasion substantially elongated whet, compared to say o& ⁇ c dimension and -with a diameter or other maximum djmen ⁇ i ⁇ n of fiom about 1 mm to about 100 mm may have utility, for example, for vascular occlusion
  • the elast ⁇ meric matrix 1W having such a fiirm ft ⁇ ? ntffflftrter rw fitiny ]T)fl ⁇ 7mm rtifittwif ⁇ nn frntr) about 3 HUHtO ab ⁇ Ut20l ⁇ m.
  • maciostructural sizes of ⁇ la ⁇ tome ⁇ o rnfltaixiOOmft lude the following crabodimc ⁇ te; compact shapes ⁇ udbi as spheres, c ⁇ bes, pyramids, tetrahedrons, eoa ⁇ s, cylinders, ta ⁇ czoids, parallelepipeds, ellipsoids* fusiibrms, tubes or sleeves, and many less regular shapes having transverse d ⁇ xn ⁇ r ⁇ to ⁇ is of from about 1 mm to about 200 nun (Ih toother eaabodimeat, these transverse dim ⁇ nsi ⁇ s are fiom about 5 mm to about 100 mm.); and sheet* or strip-like shapes having s thickness of fiom about I torn, to about 20 mm (Ia another embodiment, these thickness are from ⁇ bo ⁇ t 1 turn to about 5 mm,) and lateral dirocosions of fi
  • ffa ⁇ implantable clastomeric matrix elements of the invention have significimtly different and simpler configurations, for example, as described in the copondi ⁇ g applications.
  • the implantable device of the present invention Ox implantable devices if more than one is used, should not completely fill the aneurysm or other vascular malformation even when fully expanded in situ.
  • the folly expanded implantable devices) of the present invention are smaller in a dimension than the vascular malformation and provide sufficient space within the vascular majfo ⁇ nation to ensure vascularization, cellular ingrowth and proliferation, and for passage of blood to the implantable device.
  • the folly expanded implantable devices) of the present invention BIO substantially the same in a dme ⁇ sionasthevasoulw -nalfo ⁇ natio ⁇ , !Tn ano ⁇ ercinbod «nQit the felly expanded implantable d ⁇ vice(s) of the present invention are larger in a. dimension titan the vascular malformation.
  • ths fatty expanded implantable devices) of the present invention are smaller in volume Him. the vascular malformation.
  • tho fully expanded implantable devices) of the present invention are substmtially the same volume as the vascular malfoo ⁇ iation.
  • the fully expanded implantable dovice ⁇ s) of the present invention are larger in volume than tine vascular malformation.
  • implantable device shapes may approximate a portion of the target vascular malformation.
  • the implantable device is shaped as relatively simple convex, dish-like or honispfcerUsal ox hcmi-ellipsoidal shape mi size that is appropriate for treating multiple different sites in different patients.
  • -23- implanted elast ⁇ meric matrix ] 0 ⁇ will have a volume of no more than 95% of the biological site within the entrance thereto.
  • each implantable devices for vascular malformation applications and the like when their pores become filled with biological fluids, bodily fluids aadJox tissue in the course of time, each implantable devices for vascular malformation applications and the like substantially fill the biological sit ⁇ in which they reside and an individual implanted elastomeric matrix loo-wftl, in many cases, although not necessarily, have a volume of no toons than about 100% of the biological site within the entrance thereto.
  • an individual 100 will have a volume of no more than about 98% of the biological site within the entrance thereto
  • mii ⁇ dividi ⁇ iQ ⁇ laiited cla ⁇ inerictQaliix 100 will have a volume of no more than about 102% of the biological site within the entrance thereto.
  • Ik another embodiment when their pores become filled with biological fluids, bodily fluids and/or tissue in the course of time, sash implantable devices for vascular malformation applications and the like over-fill the biological site in which they reside and on individual implanted elastomcric matrix ioo will, in many cases, although not necessarily, have a volume of more than about 105% of the biological site within the entrance thereto. In another embodiment, an individual implanted elastomcric matrix ioo will have a volume of more than, about 125% of the biological site within the entrance thereto. Ia another embodiment, an individttdii- ⁇ tantBdelastonM ⁇ xnatrix io ⁇ wi ⁇ have a volume of more than about 150% of the biological site within the entrance thereto.
  • a further alternative morphology for elastora ⁇ ric matrix iou comprises emboli or particles useful for end vessel occlusion, capillary closure and other purposes, which emboli haw a generally spherical or other desired shape, and an average size of less than about 1 MI, for example torn about 10 ⁇ m to about SOO ⁇ m.
  • emboli have a generally spherical or other deaiied shape, and an Average size with a narrow distribution of less mac about 1 torn.
  • Such emboli may be porous, as elastomeric matr ⁇ ioo has generally been described herein, solid or hollow.
  • Elastomers for use as the structural material of ekstomerie matrix ioo alo ⁇ e, or in combination Ia blends or solutions are, in one embodiment, well-characteirized synthetic elast ⁇ m ⁇ ric polymers having suitable mechanical properties which have been sufficiently
  • elastomers for use as tho sfiractum. isitf dial of elastomerie matrix iw are sufficiently characterized s with regard t ⁇ > cbsmical, physical and biological properties as to be considered b ⁇ odurabl ⁇ and suitable* for use as wr vivo implantable devices in patients* par ⁇ c ⁇ kdy in matomals and especially in humans.
  • Elaat ⁇ meric Matrix Physical Properties O - Elast ⁇ moric matrts ioo can have any suitable bulk density, also known 03 specific gravity, consistent with its other properties.
  • the bulk density as measured pursuant to the test method described in AS 1 XM Standard D3574, maybe from about 0.005 g/cc to about 0.15 gfcc (from about 0.31 lb/ft 3 to about 9.4 Mr 5 ).
  • :ia3*wt! «reinbodiniiitt,tkeb « ⁇ S 0,127 g/cc (from about 0.5 ft/Sr 5 to about 8 lb/fl 3 ).
  • IQ another cmbodim ⁇ ii ⁇ the bvdk dematy may be from about 0 ⁇ 15 g/cc to rfjout O ⁇ I S g/cc (fiora ⁇ jout 0,93 Mj/ft 5 to i-bout 7.2 Ib/ff).
  • the bulk density may be fcara about 0.024 g/co to about 0.104 g/cc (torn about 1.5 IWSB? to about 6. ⁇ Ib/flr 1 ).
  • Hastomerie iaattfa 100 can have any suitable microscopic gvtrface area c ⁇ sisfent 20 with its other properties.
  • Those stalled in the art e.g., &o ⁇ i an exposed plane of tiie P9T OU S material, cm rou ⁇ o ⁇ - estimate the iaicroacopic surface area from the pore frequency, e.g., the number of pores per linear millimeter, and can routinely estimate the pore frequency from ⁇ e average cell side diameter in fan-
  • ioticnlated clwtome ⁇ c matrix ioofcas sufficient structural j ⁇ egritytobe self-m ⁇ poitit ⁇ a ⁇ dJEwe-staiiding ift vjiro.
  • elastomcrio matrbi Xft0 can be fiir ⁇ ishsd with ⁇ tnictutai supports suck as ribs or struts.
  • the reticulated olast ⁇ mcdc mstrix 100 has sufBcieat tensile stimgth such that it can withstand normal manual or mechanical handling during its intended application and
  • EXHIBIT 1 during post-procesaj ⁇ g steps fhat may be required or desired without tearing, breakmg, cnaabJjiig, fragmenting or otherwise disintegtatiag, shedding pieces or particles t or otherwise losing its structural integrity, HMI t ⁇ asil ⁇ atrr ⁇ g ⁇ . of the starting materials) .should not be so high as to interfere with Uw fabrication or other processing of s elastomeric matrix i «>.
  • clastomeric matrix i ⁇ w may have a tensile strength of from about 700 kg/m z to about 21,000 kg/in 2 (from about 1 psi to about 300 psi).
  • reticulated elastomeric matrix i ⁇ w has an ultimate tensile elongation of at least about 150%
  • elsetomerie matrix i oo has an ultimate tensile cteagatiort of at least about 200%.
  • Tnao ⁇ 1h& ⁇ mbo ⁇ 3amt, eiattoQ ⁇ IS ultimate tensile elongation of at least about 500%.
  • One embodiment for use in the practice of the invention is a reticulated elastoraeric matrix too which is sufiK ⁇ tly flexible and resilient, i.e., xesilieutly- ooiapressible, to euabl ⁇ it to be initially compressed under ambient conditions, e.g., at 25 0 C ftorn a relaxed coofiguration to a fiis ⁇ compact oo ⁇ figuration for delivery -via a
  • delivery-device e.g., catheter, «ndoscopo f sjringe, cystoscope, trocar or other suitable introducer instr ⁇ meiit, for delivery i ⁇ vitro and, tbi ⁇ reaf-er, to eo ⁇ and to a second, working configuration, i» situ.
  • an elastomeric matrix hss fbe ieredn described resilient-compressibility after being compressed about S- 95% of an oxxg ⁇ ud dime ⁇ sio ⁇ ( ⁇ g ⁇ compressed about 19/2OtIi - l/20tli of an original
  • Ih ⁇ thw etribodimeirt # 8ft*lostomcme mottct has the hcft ⁇ described resilisat-compressibility after being coa ⁇ ressed about 10-90% of an original dimension (e.g., compressed about 9/1 Ofh * 1/1 OtIx of an original dimension).
  • elastomeric matrix IOO has "i ⁇ silient-compr ⁇ ssib ⁇ lity", ie., i$ "resiliently-compi ⁇ ssible", when the second, workmg configuration, in vitro, is at least about 50% of the size of me
  • the lesiHent- compressibility of elastomeric matrix ioo js such that fho second, working configuration, f ⁇ wt ⁇ , is atlc ⁇ about 80% ofthe i ⁇ of& ⁇ dimcmion.
  • toe resilient-comprcasibility of ⁇ laetomeric matrix too is sucb, that the second, wnkmg configuration, in vitro, is at least about 90% of the
  • the reolient-ampra ⁇ bffity ⁇ configuration, in ⁇ itro t is at least about 91% of the size of the relaxed configuration in at least one dimemsioa.
  • an elastomeric matrix has die herein described lesilie ⁇ t- cwmpressibility after being compressed about 5-95% of its original volume (e.g., compressed about 19/2Ow - 1/20Qi of its originfll volume).
  • an ⁇ laatomeric matrix has the heroin described xedli ⁇ t ⁇ oatpi ⁇ ssibiHty after being compressed about 10-90% of its original volume (eg., compressed about 971 Oth - 1/1 Oth
  • the resili ⁇ nt ⁇ compressibility of dastomeric x ⁇ atrax IM> is such that the second, working configuration, in vivo, is at least about 50% of the volume occupied by the relaxed configuration, ⁇ haiKrfbiff eir ⁇ ctdiinenkth*. ⁇
  • ⁇ 5 matrix IW is m «k that t ⁇ esewnd, workb the volume occupied by the relaxed coufigutation.
  • the reaUient- compressibility of elastomeric matrix ioo is such that the second, working configuration; In vivo, is at least About 9Wa of the volume occupied by the relaxed configuration.
  • the r ⁇ silicnt-comprcgsibility of ela ⁇ toz ⁇ eric matrix IWis such that
  • the second, working configuration, in vivo is at least about 97% of the of the volume occupied by the relaxed configuration
  • M another embodiment, elastomeric matrix MM> can hi inserted by aa open surgical procedure.
  • reticulated elastomeric m-vtrix 100 has & compressive stre ⁇ gth of firaa about 700 to about 140,000 kg/ia 1 (fiom about 1 to about 200 psi) at 50%
  • matrix ioo has a compressive strength of from about 7,000 to about 210,000 kgt ⁇ 2 (from about 10 to about 300 psi) at 75% compression strain.
  • M another r ⁇ ibodiment, reticulated elastoineric matrix ioo has a compressive strength of ftom about 7,000 to about 70,000 lcg/m 2 (fiom about 10 to about 100 psi) at 75% compression strain.
  • Ja another erobodim ⁇ nt, reticulated elastomeric matrix 100 hr ⁇ a compressive strength of from about
  • EXHIBIT 1 7,000 to about 28,000 kg/ira* (ftom about 10 to about 40 psi) at 75% coa-pres-aon steaia.
  • reticnlsted elastomeric matrix NW hag a compression set, wheal compressed to 50% of its thickness at about 25*C, i.e., pt ⁇ suant to ASTH D3574, of not more than about 30%.
  • slastomeiic matrix ioobag a compression set of not more than about 20%.
  • elast ⁇ meric matrixoo has a compression set of not more tfean about 10%.
  • dastomeric matrix ioo has a compression set of sot more than about 5%
  • Jh another einbodiment, reticulated elastomeric matrix too has a tear strength, as measured pursuant to the test method described in ASTM Standard B3574, of from about 0.18 to about 1.78 i ⁇ flinear cm (from about 1 to about 10 Ibs ⁇ inear inch).
  • Table 1 summarizes mechanical property and other ptopts ⁇ ss applicable to embodiments of reticulated ⁇ lastomeric mfttrix ioo. Additional suitable -accfaanicaJl properties will be apparent to, or will become appaxe ⁇ t to, those skilled in the art.
  • procDS-wbility is also desirable forpost-polymeM-zation shaping and fabrication.
  • claatomeric matrix ioc has low tackiness.
  • Biodurability and Bioco ⁇ atiMtity s ' irtono r ⁇ ibodir ⁇ cnt j d- ⁇ tomers are sufficir ⁇ aybiodu ⁇ le ao as to b ⁇ imitabl ⁇ for
  • Biodurable elastomers and etestom ⁇ ric matrices have chemical, physical and/or biological properties so as to provide a reasonable expectation of bio ⁇ abi-ity, meaning that the elastomers will continue to exhibit stability when implanted in an animal, e.g., a ⁇ mmmat a for a period of at least 29o days.
  • the period of implantation - will be at least sufficient for cellular ingrowth and proliferation to commence, for example, in at least about 4-80 weeks, fo another emtodimen ⁇ eJa ⁇ mera are suffid ⁇ suitable for long-tcmimplantatdoj. by having been shown to have suchch ⁇ mic-O, physical and/or biological properties as to provide a reasonable expectation of biodnrab ⁇ ty, meaning that the elast ⁇ ura mil continue to exhibit biodurabflity when implanted for extended periods of time.
  • 30 matrix foimed by a process coH ⁇ rim ⁇ gpolymeti-i-rfion,crossli ⁇ k--ig,foaniing ⁇ ieticulation include the selection of starting components that are biodurable and the stoichiometric ratios of those components, s ⁇ ch that the clastomeric matrix retains the bifidurability of its oomponcnts.
  • elaatomeric matrix biodurability can be picauoted by tr ⁇ nhmtin ⁇ the presence and formation of chemical bonds and groupg, such
  • -29- SB egtw groups that are susceptible
  • hydrolysis ⁇ ,g., at the patients body fluid temparature and pH.
  • a curing step in excess of about 2 hours can be performed after crosslinMng and foaming to minimize the presence of free amine groups in the elastame ⁇ c matrix.
  • bioduxablo elastor ⁇ ers and elastomeric matrices are stable for extended periods of time in a biological environment Such products do not exhibit sigiificant symptoms of breakdown, degradation, er ⁇ io ⁇ or significant deterioration, of mechanical properties relevant to their use when exposed to biological environments and/cnr bodily stresses for periods of time commensurate with that use.
  • some amount of cracMng, fissuring or a loss in toughness and stiffening - at times referred to as BSC or caviiom ⁇ entaH stress cracking - may not bo relevant to endovascular and other uses as described herein.
  • elastomeric matrix ioc will become in the course of time, for example, in 2 -weeks to 1 year, walied- off or encapsulated by tissue, scar tissue or the Eke, or incorporated and totally integrated into, e.g., tho tissii ⁇ b ⁇ iDgr ⁇ air ⁇ or the lumcmb ⁇ n- ⁇ treated, En this condition, elastomeric matrix lot) has reduced exposure to mobile or circulating biological fluids. Accordingly, fhe probabilities of biochemical degradation or release of uudesired, possibly nocuous, products into the host organism maybe attenuated if not eKmioatcd.
  • the elastomeric matrix has good biodurability accompanied by goodbicHxraipatibiUrymiclitiiattheelaatornerinducesfbw, if any, adverse reactions f ⁇ vrr ⁇ .
  • the invention arc elastomers or oilier materials that are free of biologically undesirable or hazardous substances or structures that .can induce such adverse reactions or effects in vivo when lodged in aa intended site of implantation lor the intended period of implantation. Such el ⁇ stom ⁇ rs accordingly
  • *30- should either entirely laclc or should contain only very low, biologically tolerable quantities of cytotoxias, mutagens, ⁇ ffCKOQgens and/or teratogens, & another emtodimeot, biological characteristics for biodwability of elastomers to bo used for fabrication of dast ⁇ m ⁇ riic matrix l Q oinclade at least one of xesistaabe to biological degradation, and absence of or extremely low: cytotoxicity, h ⁇ moto ⁇ dtyi carcinogenicity, mutagenicity, or teratogenicity.
  • FIG. 1 the schematic block flow diagram shown gives a broad overview of apioceas according to thaiav ⁇ itton whereby an implantable device comprising a biodurable, porous, reticulated, ⁇ laatomcric matrix IW can ha prepared fiom xxw elastomer oi elastomer reagents by one or another of several different process routes,
  • Ia a first route, elastomers prepared by a process according to the invention, as described Iiiseiri, are rcQdered to con ⁇ rise a plurality of cells by using, e.g., a blowing agoflt or agents, einploy ⁇ - ⁇ ag their pr ⁇ paraJioa. fopartictdar, staa ⁇ aig materials 4W, which may compose, for example, a polyol conjponent, aa isocyanata, optionally a crosslirJc ⁇ Tj and aaydftsired additrvessucl.
  • a blowing agoflt or agents einploy ⁇ - ⁇ ag their pr ⁇ paraJioa. fopartictdar, staa ⁇ aig materials 4W, which may compose, for example, a polyol conjponent, aa isocyanata, optionally a crosslirJc ⁇ Tj and aaydftsi
  • polyraerizatiofl step 42 « either v ⁇ Ox or witiiout sigoifioant foaraing or other por «-g ⁇ oerating activity.
  • the starting materials aro selected to prowd ⁇ desirable mcwhamcalprc ⁇ erties and to e ⁇ bmico bio wr ⁇ biodurabOity,
  • step 4 ⁇ The clastot ⁇ -aic polymer product of step «ois then characterized, in step 4 ⁇ as to Chemical nature and purity, physical and mechanical properties and, optioaaHy, also as to biological characteristics, all as described ab ⁇ vo, yielding well-chfiractesdzed elastomer 500.
  • the process or ⁇ xe prod ⁇ ct as indicated by forked arrow 5i ⁇ - Selecting elastomer soo to be sorvent-solubie, for exmxsple by ens ⁇ ritig that it fa not crossli ⁇ ked, enables clsstomet 500 to be closely analyzed for effective process control and product characterization,
  • the elastoroeric polymer reagents employed in starting materia] 400 may be selected to avoid adverse by-products or residuals mid purified, if necessary, step 530- ⁇ Oly ⁇ ier synthesis, step S4O, ia then conducted oa the selected and purified starting materials and is conducted to avoid generation of adv ⁇ rso by-products O j residuals.
  • step zwja then obaracterized* step sm ea described for step 48 ⁇ to feciiit ⁇ t ⁇ production of a high quality, well-defined product, weU-cfcaact ⁇ rized elastomer sou.
  • step sm ea the char ⁇ te ⁇ ation results are fed back for process control as iodicated by forked arrow sso. to f ⁇ ci
  • elastom ⁇ i ⁇ are synthesized pursuant to known methods and subsequently rendered porous.
  • An. exemplary elastomer of this type is BXONATE® SOA polyarethane elastomer, The el ⁇ Stoo- ⁇ i so ⁇ cm be rendered porotts ⁇ e.g., by a blowing agent employed in a polymerizatloa reaction or ia a post-polymerization step.
  • the invention provides, in one embodiment, a reticulated biodurable clastomeric matrix compris ⁇ ng polymeric damqits which arc specifically designed for the purpose of biomedical implanta ⁇ on.
  • K comprises btodur ⁇ lepolyineric materials and is prepared by a process or processes which avoid chemically changing the polymer, the fo ⁇ nation of undesirable by-products, and residuals comprising undesirable uureact ⁇ d starting r ⁇ aterialg.
  • foams comprising polyitfethawss and created by foa ⁇ wn techmques t ⁇ ay not bo appropriate for long-term endovasc ⁇ kr, orthopedic and related ⁇ plications because of, e.g., the presence of ujodcsirable unreacted starting materials or undesirable by-products.
  • woll-charactcri ⁇ ed elastomer SOO is thermoplastic with 8 Vicat softening temperature below about 12O 0 C and has a molecular weight facilitating solvent or melt processing.
  • ⁇ pother embodiraent, well-characterized elastomer soo is , tiwrmo
  • Elastomei 500 can convor ⁇ ently be firmi ⁇ ied i ⁇ divided fbnn st this stage, e.g., as pellets, to facilitate subsequent processing.
  • step 620 yielding porous elastomer 640-
  • step ⁇ 0 employs a process -which -BSVBS no undesirable residuals, such as residuals adverse to bioduri-bflity, and does not charig ⁇ the chemistry of the elflstojner soo.
  • Ia mother embodir ⁇ ent, porous biodurebla elastomer ⁇ o can be washed wtii solvent, for example a volatile organic such as hexane orisopropauol, and air dried.
  • Fabrication step 620 may include a more or less complex molding step or feature, for example to provide bulk stock in the form of a strip, roll, block or the lifc ⁇ of porous biodraable elastomer MO-
  • Poro ⁇ s biodurrible elastomer M o may be used to maau&cture ⁇ lagtomeric matrix IW, far example by cutting to s desired ahapo aod size, if necessary.
  • process-related cliaractcsistics refeniag to a process used &r the pr ⁇ paiatioi- of the elastomer of the solid phase i ⁇ forbiodurabUity of elastomers to oeusedf ⁇ rMjricatiouofel ⁇ toKie ⁇ ciaat ⁇ xiofliiicludeoneorriore of: piocess reproducibility; process control for product consistency, s ⁇ avoidance or substantial removal of adverse impurities, reactants, by-products, oligomers md th « like.
  • the starting r ⁇ aterial(e) to&y be fiirther processed atid/br characterized to eahaacc, provide or document apropcity relevant to biodurability.
  • ⁇ naaothercml»diment,thefequifflteprtpp ⁇ ofe-a ⁇ cr ⁇ ers db ⁇ r ⁇ ctcdz ⁇ d as appropriate and Ha» process features can be adapted or controlled to, enhance biodurability, purs ⁇ a ⁇ t to the teachings of the present specification,
  • Elastomeric Matrices fromElastciimerPolymciizaiio ⁇ , Crosslinfeing end Foaming Ia further embodiuwnte, tho inve ⁇ dion provides & porous biodurable elastomer aad a process for polymerising, crossli ⁇ J ⁇ g aad foaming the same v ⁇ i ⁇ & cm bo used to produce a biodurable reticulated elastota ⁇ ric matrix as described herein, i ⁇ another ⁇ bodir ⁇ nt, rcticwlation follows.
  • the -nveoiiou provides a process for preparing a biodurabt ⁇ et ⁇ stomeric polyuflstbaae matrix whioi compriaes syntbe ⁇ isdag the matrix from a polycarbonate polyol coraponont and an iso ⁇ yaaata component by polymerization, ⁇ osat ⁇ aikmg and foaming, thereby ft ⁇ rarjg pares, followed by neticuMcmofa j e f ⁇ am to provide areticu ⁇ ated product, lbs product i ⁇ designated as a polycarbonate polyurefliane, being a.
  • the process employs at least one polyol component for foe ptnposes of this application, the term, "polyol component” foelu ⁇ es molecfttles w ⁇ tp ⁇ sing, on tbe average, sfco ⁇ t % hydnxxyl groucps per molecule, i,e, 5 & difit ⁇ ctio ⁇ al polyol or a diol, as well es those molecules comprising, on the average, greater than about 2 hydroxy! groups per molecule, i.e., a polyol or a wiM- ⁇ i ⁇ ctional polyol.
  • polyol component foelu ⁇ es molecfttles w ⁇ tp ⁇ sing, on tbe average, sfco ⁇ t % hydnxxyl groucps per molecule, i,e, 5 & difit ⁇ ctio ⁇ al polyol or a dio
  • Ex ⁇ plary polyols can compiis ⁇ , on the average, from about 2 to about 5 hydroxy! groups per molecule.
  • the procros ⁇ npZoys a difiiQCtioi-al polyol compoH ⁇ t B.
  • tt ⁇ s embodiment because th « hydroxy! gcoi ⁇ p fiaictionality of the diol is about 2, it does not provide the so-called "soft segment” with soft ecgrae ⁇ t crosslintirtg.
  • the process employs & raiW-fij-ictiooal polyol component in sufficient quantity to provide a co ⁇ tiell ⁇ d degree of soft segment crossUD-dng.
  • Ia ?aoth( ⁇ embodMnent,tliQ process provides suffident soft segtn ⁇ nt ciosslioking to yield a stable foam
  • the soft segment is composed of a polyol component that is generally of a rclatively low ⁇ noleoular weight, typically ftom sbout 1,000 to about 6,000 Dalton ⁇ .
  • these polyols are genernlly liquids or low-melting-point solids.
  • This soft flegmeiit polyol is temiinaled with hydroxyl gfoiips, either primaty or secondaiy.
  • IQ mwthi-r ⁇ mbodimeot a soft segment polyol componant has about 2 hydxoxyl groups per mol ⁇ crde.
  • ⁇ anoHher embodiment, a soft segment polyol con.pone.it lias greater than, about 2 hydroxy!
  • the average n ⁇ tmber Of -jyd ⁇ xyi groups pttr molecule in the polyol component is about 2.
  • the millge number of bydroxyi groups pear molecule in the polyol component is great ⁇ ritwn sibout 2.
  • lnon ⁇ mbodiment,th ⁇ pol ⁇ lcoi- ⁇ ent «w ⁇ iisc ⁇ a t ⁇ rt ⁇ aiy ca ⁇ b ⁇ ! ⁇ i3inkagc.
  • the polyol component is apolyetbw polyol, polyester pouyoi, polycarbonate polyol, hydrocarbon polyol, polys ⁇ oxane polyol, poly( ⁇ flier-coHest ⁇ f) polyol, polyCeSier-co-carbouate) polyol, poly( ⁇ & ⁇ frhy ⁇ Cttto ⁇ m) polyol, ⁇ oly( ⁇ m ⁇ r- co-siloxan «) polyol, poly ⁇ estex ⁇ oo-carbooate ⁇ polyol, poly(estar-co ⁇ nydroc&xboa) polyol, p ⁇ ly(ester-ca» ⁇ loxane) polyol, poly ⁇ oarbonatfr-co-hy «toociabOD) polyol
  • Polyethtt-type poiyols arc oligomers oC e.g., dkyl ⁇ ae ⁇ sa such as ethylene oxide or propylene oxide, polymerized with glycols or polyhy ⁇ ic alcohols, fb& latter to result in hy ⁇ roxyl mnctio ⁇ alitics greater than 2 to aHow for soft segment crossfi ⁇ kmg.
  • dkyl ⁇ ae ⁇ sa such as ethylene oxide or propylene oxide
  • Poly* ⁇ ter-type polyols are oligomers of; eg., fine teactionptoduct of a caiboxylic acid with a glycol or triol, such as ethylene ⁇ yocA adipat ⁇ propylene glycol adipate, b ⁇ tyl ⁇ ne glycol adipatc, dicthyle ⁇ glycol ad-pat ⁇ phtlislaks, polyW ⁇ rolactono and castor oil.
  • the rca ⁇ tants include those with hydroxy! fuactionalities greater than 2, e.g., polyhydiic alcohols, soft, segment crosslinldng is possible.
  • Polycarbonate-type polyols are biodurable and typicaGy result from the leactio ⁇ , with a carbonate monotter- of one type of hydrocarbon diol or, for a plurality of diola, hydrocarbon diols each with a different hydrocarbon chain length behveen.
  • the hydioxyl groups The length of the iry ⁇ roca-toac- ⁇ the hydrooarbo ⁇ . chain length of the original tUol(s).
  • a difimctio ⁇ al polycarbonate polyol ca ⁇ be made by nsacting 1,6-he ⁇ aaes ⁇ ol 'with s carbonate, such as sodium, hydrogen, carbonate, to provide the polycarbonate-type polyol 1 ,6-hexair ⁇ C-i ⁇ l carbonate.
  • the molecular weight for the co ⁇ unercial-svailablepiod ⁇ cts of this reaction varies fir ⁇ n about I 1 OOO to about 5,000 JDaltons.
  • ⁇ f th ⁇ polycarbonate polyol is a solid at 25 fl C, it is typically melted prior to further processing.
  • liquid polycarbonate polyol co ⁇ or ⁇ t CSB - p ⁇ pa ⁇ d &om & mixture of hydrocarbon diols eg,, all three or suay bioary comVi ⁇ ation of 1,6-he ⁇ an ⁇ diol, cyclohexyl dim ⁇ fh-mol and l,44>utorwdioL "Witiioutbejttg bound by aaypartlciular
  • misturts with, other hydroxyl-comprising0 materials, fox cxan ⁇ l ⁇ , oyclohcxyl trimctliaiiol and/or outaaetriol can be reacted with tht caifeonat ⁇ along with the heoca ⁇ p triol.
  • Polys ⁇ oxanc polyols are oligomers of, e.g., alfcyl and/or aiyl substituted - ⁇ loxanes such as d ⁇ netbyl siloxane, diphenyl siloxane or methyl phenyl siloxans, comprising, hydroxy! ⁇ nd-gr ⁇ ups.
  • a particular tj-pe of polyol need not; of course, be limited to those formed fiom a single monomelic unit.
  • a polyether-type polyol can. be formed from a mixture of ethylene oxide sod propylene oxide.
  • copobuiejs or copolyols canbe ibmed from a ⁇ yofthc above polyols by method taiown to those ia the art
  • 25 binary conipo ⁇ at polyol copolymers caa be tiaed: poly(ether-co-eater) polyol, poly(ethcr-co-carb ⁇ na ⁇ fc) poljOl ⁇ polyCctiiw-co.bydrooartjon.) polyol, poly(ethei-co- siloxanc) polyol, poly( ⁇ ster-co-carbonate) polyol, polyCesftcr-co-hydTOcsrbon) polyol, poly(ester-co-siloxane) polyol, poly(caAoiiate-co-hydrocaib ⁇ D) polyol, poly(c ⁇ rbo ⁇ ste- co-siloxanc) polyol and poly(hyd ⁇ ocarboa- ⁇ ! ⁇ -- ⁇ loxan6) polyot
  • ⁇ oly ⁇ ether-co-ester) polyol can be formed fiom units of polyctbers formed fiom ethylene oxide copolyaieriz ⁇ d with ⁇ u ⁇ ts of polyester cs ⁇ piising ethylene glycol adip ⁇ te.
  • the copolymer is a poly ⁇ ctUer'Co-catbor-ate) polyol, polyfethw-oo- hydiocarboa) polyol, pory(ether-oo-siloxaae) polyol, poly(c ⁇ mate-co-hydrocarbon)
  • the copolymer is apoly(caibott8te-co- faydrocarbon) polyol, poly( «ffb ⁇ nat ⁇ -s ⁇ oxaEe) polyol, poIyObydr ⁇ cflrtion-co ⁇ aoxan ⁇ ) polyol or mixtures thereof.
  • the cc ⁇ dymer is apo3y(caibonate- p o-hy ⁇ i ⁇ caiboo) polyol
  • the polyol component us apolyethw polyol, polycatbocat ⁇ polyol, hy ⁇ oc ⁇ boii polyol, polyailoxaae polyol, polyCe&w-w-ca&onate) polyol, poly(efIr ⁇ H! ⁇ -hydn)carboo) polyol, po!y(efhtf «co-sBoxaae) polyol, poly(carboEUit ⁇ c ⁇ y ⁇ -inea*on) polyol, poly(ca ⁇ oi ⁇ aieHj ⁇ -8il ⁇ xair ⁇ ) polyol, poly ⁇ .ydrocaiboQ-co-syoxan ⁇ ) polyol or mixtures thsrw£
  • the polyol compon ⁇ at is complaintycsd ⁇ aiate polyol, tydiocaiboa polyol, polysiloxaa ⁇ polyol
  • the polyol coxntpou « ⁇ t is apolycatbonats polyol, polyCcfttbonst ⁇ -co-hydnocarbon) polyol, poly(caibona$e-co-sao ⁇ ane) polyol, polyO-ydwcacbon-oo-silox- ⁇ ie) polyol or mixtures thereof
  • the polyol component is a polycarbonate polyol, poly(c«1 ⁇ ni-Ue-co-]hydrocaibo-i) polyol, poiy(caAoi-ate ⁇ io-sil ⁇ Mcane) polyol or mixtures thereof, ⁇ ano&ci emlsodimcu ⁇ tfac polyol co ⁇ onsntisaF ⁇ lycarbonate polyol.
  • Furth ⁇ nnor*, in another ⁇ abodim ⁇ at, mixtaies, adroixtaees and/or blmds of polyols and copoiyols can be used in the ⁇ lastomcric matrix of the present invention.
  • Ih another c ⁇ ibodimon ⁇ tti ⁇ molewlar weight of liia polyol is varied.
  • the functionality of the polyol is varied.
  • Ih another embodiment, as either diftaictioflfll polycarbonate polyols or difimctiioiialhydrocaibonpolyO-S cannot, on their own, induce soft segment crossliuldQg, hi ⁇ fci ⁇ rfimctioi ⁇ lityia i ⁇ tcoduoedii ⁇ to ibs foxmidatioiithFoi ⁇ fc ⁇ iiao ofa ⁇ am TOCt ⁇ ndet component with a hydroxyl group flmcticmality gt ⁇ ster than about 2.
  • U ⁇ sr functionality is introduced through the ase of an isocya ⁇ atc component with ffliisooyaMt ⁇ group funcdoiidity greyer than about 2.
  • the process also employs at least cmffis ⁇ cya ⁇ ate component mi, op ⁇ onaEy, at least O ⁇ diatocsrtet ⁇ dtarcca ⁇ jpoBe ⁇ t to pwv ⁇ d ⁇ so-caJlled 'lia ⁇ sog ⁇ . ⁇ Qt 1 ',
  • isoc ⁇ anatc co ⁇ xm ⁇ nt includes molecules co ⁇ ris ⁇ -& «Q the average, aboot2.aooyaoate grw ⁇ perixiolecwle aswelliisiJMjse molccwlw cojcopiisitig, on the average greater than about % is ⁇ cya ⁇ ate groups per molecule.
  • Ttie jsotyaaatfc groups of ⁇ c isocyaflats compoae ⁇ t are rcactivo with, reactive bydiogw. groups of the other ingredieots, e.g., with hydrogen bonded to oxygen in hydroxyl groups aftd vvitfa. hydrogen bonded to nitrogen in aauQe gto ⁇ S of the jwlyol cc»inponr ⁇ t, ⁇ hamcxteiMlor, cr ⁇ 3sll ⁇ er sn(!/oi: water. ⁇ a ⁇ artic?i-!i ⁇ , wbe ⁇ water is pwsent, e-g.
  • the water Caa react witii- aa isooysaate group of the isocyanate component to form aa mia ⁇ , which oaa react with another isocysaate group ⁇ to fo ⁇ a urea moiety.
  • the final polymer is a pol ⁇ W ⁇ tha ⁇ ttca because it ca ⁇ coataj ⁇ ⁇ r ⁇ &me moieties and t ⁇ wa moieties.
  • a "polyurefoan ⁇ " foa ⁇ ed &om sn isocyanate con ⁇ oncnt includes ftpolyurfttha-ie, apolyureliane-urea, and their ttdxtarcs.
  • a polyvarcthane of the x ⁇ veott ⁇ fc ⁇ n ⁇ d uouiea isocyan ⁇ t ⁇ component using; water aa a bloW3 ⁇ Bgaat ⁇ ropfl $ es,o: ⁇ & ⁇ - ⁇ age,m ⁇ ⁇ ao ⁇ * ⁇ nbodimw ⁇ w aywaggar ⁇ t ⁇ ff ofisocywaat ⁇ groiips per molecule in the ;socyanatccon3ponej-.tis stoout2.
  • 3n ' acothW ⁇ ratotitoeiat f tho ⁇ eragerambWofte iipxyenatccoaipoi- ⁇ t is greater tl-to about 2,05, Ih mot ⁇ erobodimont
  • the average ntcmber of feocyaoat ⁇ groups per molecule in the isocyauate component is greater than 2.1.
  • the average number of isocyanate groups per molecule in the isocya ⁇ ato component is greater that* about 24-
  • the average nuiriber of isocyaaate groups per molecule in $ the isocyanaie co ⁇ ipon ⁇ nt is greater Hum about 22.
  • the isocyanate index a quantity well known to those in the att, is the mole ratio of the number of i ⁇ ocyauate groups in. a ib ⁇ mda ⁇ on available Sat reaction to the number of groups in the fbr ⁇ ralstion that ace able to react wjifc. those isocyaaate groups, e.g., the reactive groups of dioj(s), polyol coi ⁇ poneotfs), cfcaui etf ⁇ nd ⁇ rt ⁇ ), and water, wbeao present.
  • the isocyanat ⁇ macs is fiom about 05 to 1.029.
  • the isocyaaate index is ficom about 0-9 to 1.028.
  • the isocyaaate index is from about 0.9 to about 1.025.
  • the isocyanatc index is fitnn about OS to about 1.02, Sa. another embodiment-, the isocyaoatoS index is from about 0.93 to about 1.02.
  • the isocyansl ⁇ index is ftoxn about 0.9 to about 1.0.
  • the isocyaaate index is from about QS to about 0,98.
  • Exemplary d ⁇ s ⁇ cya ⁇ ates include aliphatic diiso ⁇ yanates, isocyanates comprising aromatic groups, the so-called “aromatic diisocyaaates", and mixtures thereof.
  • Aliphatic0 diisooy ⁇ at ⁇ m cludetetramethylm ⁇ dii ⁇ o> ⁇ lohwane»l J 4Mdnswyaiiate
  • F l-exaincth(yieiie d ⁇ socyaoate, isopnorone d ⁇ socyanate, moQiylene-bis-Cp-oyclohexyl isqcyanate) (" ⁇ i ⁇ MDT*), and mixture; thereof.
  • Aiotnatic diisocyanates include p-phcnyleno d ⁇ socyanate, 4,4'-diphenylmethane diisocyanate ⁇ "4,4'-MDX”), 2/'H%hea ⁇ e1h ⁇ ediisocyai--ite ("2,4'-MDr% 2,4-toltisii ⁇ d ⁇ socyaaate5 (“2,4-TD ⁇ 1 ), 2,6-tolueae d ⁇ socya ⁇ ate( H 2,6-TI»T').
  • Exemplary isocyanate cotopone ⁇ ts coiajiris ⁇ ig, cm the average, greater then about 2 isocyaoate grov ⁇ s par molecule include an odduot of hexamethylene d ⁇ socysnato and water comp ⁇ ing about 3 isooyaa&tc groups, available ⁇ s ⁇ mmw ⁇ aSy asDBSMQDUR®0 NlOO fior ⁇ Bayer, and a trimer of hexamethylen ⁇ disocys ⁇ ate comprising about 3 isocyanat ⁇ graups, available commeici ⁇ dly as MONDUR® N3390 j&om Bayer.
  • Ia oae embodiment & « isoqyanate component co ⁇ toina a l ⁇ xtuie of at least about 5% by weight of 2,4'-MDI -with Hw balance 4,4VMDI, thereby excluding the polyether or polycarbonate poly ⁇ r ⁇ thanes having l «ss than 3% by weight of 2,4'-MDI disclosed by
  • the isocyanate component contains a -fixture of at least 5% by weight of 2,4'-MDI vvith the balance 4,4'-MDI.
  • the isocyanate component contains a mixture of fiom about 5% to about 50% by weight of 2,4'-MDI with the balance 4,4' ' MDL fa another embodiment, the isocyanate component
  • the bocyanato component contains a mixture of from about 5% to about 40% by weight of 2,4'-MDI with fte balance 4,4'-MDL to.
  • the isocyanate component contains a mixture of from 5% to about 40% by weight of 2,4'-MDZ with Uw balance 4,4'-MDL
  • the isocyanate0 component contains a mixture of fiom 5% to about 35% by weight of 2,4'-MDI with the balance 4,4 -MDL
  • 5 Suitable dusocyanates include MDI.
  • ISONATE® 125M certain members of the PAH® series from Dow and MOKDUR M frcsn Bayer
  • isocyanates containing a mixture of 4,4'-MDI and 2,4'-MDi such as K ⁇ BINAXE® 9433 and RUB-NATE 9253, each &om Hu ⁇ tst ⁇ n, snd ISONATB SO OP ftom Dem
  • TDl e.g., from Lyondcdl Corp.
  • Suitable i ⁇ ocya ⁇ ate components comprising, eax the. average, greater £ha ⁇ about 2 isocyanatc groups per molecule, include the foHowing modified dipbcaylmethace- d ⁇ socyanaie type, each available femx Dow: ISOBIND® 108S 1 with an isocyanate group
  • 3D isocyanate groups per molecule include the following, each available Jfrofli Huntsman: RUBINATE® 9433, with an isocyanate group functionality of about 2.01; and RUBXNAXE 92SS, with an. isocyanate group nmcticawlity of about 2.33.
  • Exe ⁇ lacy chain extenders include diol ⁇ diammcsj alkanola-n ⁇ ies and -nixt ⁇ ies thereof.
  • tiu chain extender is m aliphatic diol having fio ⁇ n 2 to 10
  • tfa ⁇ diol chain extender is selected fiom ethylene glycol, 1,2- ⁇ ropane diol, 1,3-propanediol* 1,4-b ⁇ rtane diol, 1,5- ⁇ entanediol, diethyl ⁇ ne glycol, t ⁇ ethyle ⁇ e glycol and mixtures thereof Ia another embodiment; the chain extender is a diamine having from 2 to 10 carbon atoms, In another embodiment, the
  • $ diamine chain extender is selected from ethylene diamine, l ⁇ -dte ⁇ i ⁇ ut ⁇ ne, 1,4- diaminobutane, 1,5 d-fflnmopentane, l ⁇ -diaminobexan ⁇ , 1,7-diat ⁇ iaoh ⁇ p.ano, 1,8» diaminooctano ⁇ isophoron ⁇ diamine and mixtures thereof,
  • the chain extender is an alk ⁇ nol amine having from 2 to 10 carbon atoms
  • the alkanol amine chain extender is selected fiom diethanolamine,0 t ⁇ efbuanola ⁇ -i ⁇ e, isopropanolamiiie, ⁇ tfayiethanolatnine, metfryl ⁇ -sthanolaaiine, di ⁇ thylethanola ⁇ ilnc and mixtures ⁇ hereof.
  • chain extenders include the JBFFAMINE® secies of diamines, triamincs and polyeth ⁇ ramines available fiom Huntsman, VBRS AMIN® isophoxone dia ⁇ ne fiom Creanova, the VERSAlffiK.® series of diamines available9 tiwm Air Products Corp. (Alleotown, PA), eth-molaminc, diethylethanolarojne and isopiopanolamin ⁇ available fiom Cow, find various chain extenders fiom Bayer, BASF and UOP Corp. pes Flaines, IL).
  • a small quantity of an optional ingredient such as a multifunctional hydroxyl compound or other crossBnker having a functionality greater than %0 e.g., glycerol, is present to allow crasslinking.
  • the optional multi-functional crosslinker is present x ⁇ an amount just sufficient to achieve a stable foam, i, ⁇ , a foam that does not collapse to become nc ⁇ -f ⁇ aniL-kc.
  • poryfunc ⁇ onal adduct ⁇ . of aliphatic and cycloaliph-itic isocyanates can be used to ioipaitcBjsalir ⁇ ang in cwmbinationwi&an ⁇ c dii-iocyanates.
  • polyf ⁇ aotio ⁇ al adducts of ⁇ lipiaticandcycloa-iphaticisocya ⁇ attti canbeused to impart crosslinking in combination with aliphatic dtisocyaaatos.
  • the process employs at least one catalyst in certain embodiments selected from s blowing catalyst, e.g., a tertiary amino, a gelling catalyst, e.g., dibntyltin dilaurato, and mixtures thereof.
  • s blowing catalyst e.g., a tertiary amino
  • a gelling catalyst e.g., dibntyltin dilaurato
  • tt ⁇ catalyst e.g., a tertiary amino
  • a gelling catalyst e.g., dibntyltin dilaurato
  • tt ⁇ catalyst e.g., dibntyltin dilaurato
  • Exemplary tertiary amine catalysts inohjde me TOTYCAT ⁇ lin ⁇ fixr ⁇ Toyo Soda CTo. (Japan), the TEJCACAT® line J-rom Texaco Chemical Co.
  • organotin catalysis include the FOMREZ® and FOMEtBZ UMB Uncs ftom Wtco Corporation (Middlebiuiy, CT), the COCURB® and COSCAT® lines fiom Cosan Chemical Co. (Carlstadt, NJ), and theDABCO® andPQLYCAT® lines from Air Products.
  • the process employs at least one surfactant.
  • surfactants include DC 5241 from Dow Coming (Midland, MI) and other non-ionic organ ⁇ silicoflsa, sacjh. as the polyditaethylsiloxane types available from Dow Ceasing, Air Products aad General Electric (Waterfotd, KY).
  • Crosslinked polyurethanes may be prepared by approaches which include the prepolymcr process and tbo one-shot process. An embodiment involving a prepolytaer is as follows.
  • the prepolymer is prepared by a conventional method from, at least one isocyan_i£e component (e.g., MDI) and at least one multi-functional soft segment material -with a functionality greater than 2 (e,&, a polyether-Tjased soft segment -with a fbnctionality of 3).
  • at least one isocyan_i£e component e.g., MDI
  • at least one multi-functional soft segment material -with a functionality greater than 2 e,&, a polyether-Tjased soft segment -with a fbnctionality of 3
  • fheprepolym ⁇ r optionally at least one catalyst (e.g., dibutyltin dil-cnrato) and at least one d ⁇ nctional chain extender (e.g, t I,4 ⁇ butancdiol) are admixed in amixingvessd to C ⁇ or crosslink tii ⁇ inixtr ⁇ e.
  • Ih m- ⁇ thCT «mbodi--ient 5 C3 ⁇ ssunking takes place in & mold.
  • aosslinkmg and foaming, i.e., pore fbrmation, IaKe place together.
  • crossliaki ⁇ g and f ⁇ £imimg take place together in a mold.
  • the so-called “one-shot” approach may be used.
  • a one-shot ombodimont requires no separate prepolymor-making step.
  • the ingredients are bested before they are adrnixed _n another embodimctit, -the ingredients are heated as they are admixed.
  • crossliiikingtokes place i ⁇ a itiold, in another embodiment, foaming and crosslinking take place togcfli ⁇ r.
  • ciossli ⁇ king and foaming take place together in a mold.
  • all of the ingredients except for the isocyanate component are actajixed in a mixing vessel.
  • the isocyanate component is then added, e.g., wtf ⁇ iugb ⁇ peed stixring, and crosslinking and foaming ensue.
  • this foaming mix i$ poured into a mold and allowed to riso,
  • the polyol component is admixed -with the isocyanate component and other optional additives, such as a viscosity modifier, surfactant aad/or
  • the p ⁇ lyol component is a liquid at the admixing temperature or over the admixing temperatare range.
  • the polyol component is a solid, therefore, the polyol component is liquefied prior to admixing, e.g., by heating.
  • the polyol component is a solid, therefore, the admixing temperature or admixing temperature range is r-dsed such, that the polyol component is liquefied prior to admixing.
  • a second liquid is formed by adtcdxing a blowing agent and optional additives, ⁇ ch as galling catalyst and/or blowing catalyst Then, the fiist liquid and the second liquid are admixed in. an admixing vessel and then, foamed and crossliijlc ⁇ d.
  • the invention provideg aprocesaforpreparing afl ⁇ xiblc polyoretfaane biodurablc matrix capable of being reticulated based on polycarbonate polyol component sod isocyaaato component starting materials.
  • a porous biodurable elastojc ⁇ rpolymerization process for making aicaiKent polyurethanc matrix which process composes admixing a polycarbonate polyol component and an aliphatic isocya ⁇ ate component, for example H u MDI
  • the foam is substantially ftee of isocyam ⁇ rate linkages, thereby excluding thepoly ⁇ -ei or polycarbonate polyurcthanes having isocya ⁇ urate linkages disclosed by Brady '550.
  • me foam has no isocyanurate linkages.
  • Ih aiujthcr embc ⁇ --mr ⁇ t,ihc foam is subsi-mtiaUy free of biuret l ⁇ Lx another embodiment, the fbambas no biuret linkages, In a ⁇ er embodiment, the foam is substantially free of allophanate linkages.
  • the foam has no aHophaaate liflkagcg
  • th* foam is substantially free of isocyanurate and biuret linkages.
  • the ⁇ sam has so isocysmurate and biuret linkagw.
  • the &am is substantially feec of i ⁇ cyanuraicafldallopba ⁇ atoHnkages.
  • the fbam has no i ⁇ ocyanurato and aHophanatc linkages
  • the foam is substantially free of allophanate and biuret K ⁇ kagcg.
  • the foam has no aUophanate and biuret linkages.
  • the foam is substantially free of allophanate, biuret and isocyanurate linkages, Iu another embodiment, the foam has no allophanate, biuret aMisocyaauraie linkages. Without being bovmd by any particular theory, it is thought that the absence of aUophaaate, biuret and/or isocyanurate linkages provides a ⁇ enhanced degree of fle ibility to the elastcmeiic matrix because of lower crosslmkmg of the hard segments. " ⁇ n certain embodiments, additives helpful in achieving a stable foam, for example,
  • clastomedc matrices of various densities e.g., from about 0.005 to ⁇ out 0.15 gfcc (fiora about 0.31 to about 9A lb/fl?) are produced, ⁇ a ⁇ density is controlled by, ⁇ .g., the amount of blowing or fbaa ⁇ g agent, th* isocyanate index, the iaocyanate component content in the fo ⁇ nulatioa, the reaction exotherm, and/or the pressure of the foaming environment.
  • Exemplary Wowing agents include water and the physical blowing agents, e.g., volatile organic chemicals such as iydrocarbonii, ethanol and acetone, and various flttorocarbons and tiieir mow environmentally friendly replacements, such as nydpofiuorocarbons, cMorofluorocaibons and nydrochloiofluorocar ' borifl.
  • the reaction of water with an xsocyaaate group yields carbon, dioxide, which serves as a blowing agent.
  • combinations of blowing agents such, as water with a fi ⁇ orocarbon, can be used in certain embodiments.
  • the amounte of the other components present, by weight, in a fo ⁇ aulation are as follows: from about IG to about 90 parts (or grams) isocyanate component (e.g., MDIs, thefr mixtures, HijMDI) with an isocyaaate index of jEcom about 0.85 to about 1.10, from about O.S to about 5,0 parts (or grains) blowing agent (e.g., water), from about 0.1 to about 0.8 parts (or grams) blowing catalyst (e.g., tertiary ami ⁇ e), from about 0.5 to about 2.S parts (or grama) surfactant, and ftor ⁇ about 03 to about 1.0 parts (or grains) cell opener.
  • isocyanate component e.g., MDIs, thefr mixtures, HijMDI
  • blowing agent e.g., water
  • blowing catalyst e.g., tertiary ami ⁇ e
  • the actual amount of isocyanate component used is related to and depends upon the magnitude of the isocyanatc index for a particular foimulat-On.
  • the amounts of the following optional components, when present in a formulation are as follows by weight: up to about 20 parts (or grams) chain extender, up to about 20 parts (or grams) crosslinker, tip to about 0.3 parts (or grams) getting catalyst (e.g., a compound comprising tin), tip to about 10.0 parts (ox grams)
  • -44- physical blowing agent e.g., hydrocarbons, ethanol, acetone, fluorocarbons
  • up to about 8 partg (or grams) viscosity modifier e.g., hydrocarbons, ethanol, acetone, fluorocarbons
  • Matrices with appropriate properties for the memeposes of the invention a$ d ⁇ tfirmincd by testing, for example, acceptable compression sat at human body temperature, airflow, tensile strength and compressive properties, can then be reticulated.
  • the gelling catalyst eg., the tin catalyst
  • the tertiary amine catalyst comprises one or more non-aromatic amines.
  • the reaction is conducted ⁇ o ⁇ at the tertiary amine catalyst, if employed, is wholly reacted into th « polymer, andrcsjdties ofsajn ⁇ are avoided.
  • the gelling catalyst is omitted and, instead, higher foaming temperatures are used,
  • ingredients for the polymerization process are selected so as to avoid or minimize the presence in the end product dast ⁇ t ⁇ erie matrix of biologically adverse substances or ' substances susceptible to biological attack.
  • An alternative preparation embodiment pursuant to the invention involves partial or total replacement of water as a, blowing agent with water-soluble spheres, fillers or particles which are removed, e.&, by washing, extraction or melting, after Ml ctosslhM ⁇ s of the matrix.
  • open-cell materials or foams i ⁇ contrast, porous materials fioa.
  • wHcnroany i.e., at least about 50%, of the cell walls nave been removed are faiowa as “reticulated” or "at least partially reticulated”.
  • -45- toe cell walls have been removed are tox ⁇ wn as "further reticulated”. If most, i.e., at least about 80%, or substantially all, Ie,, at least about 90%, of the cell walls have been removed then the poipus material that remains is known as “substantially reticulated” or "My reticidated”, respectfully.
  • ⁇ twiU be tmdetstood that, pureuaut to this art usage, a 5 reticulated material or foam comprises a network of at least partially open interconnected colls, thereby excluding the n ⁇ weticulate ⁇ polyethHr or polycarbonate polyuretiumes disclosed by Brady '550.
  • Reticulation generally refers to a process for removing sad* cell walls not merely rupturing tJwm. by a process of crumbing. Moreover, undesirable crushing creates0 debris that must be removed by farther processing.
  • Retioulatio-ir ⁇ ay b* effected, for example, by dissolving out the coll walls, known variously as “chemical reticulation” or “solvent reticulation,”; or by burning or exploding out the cell walls, known variously as “combustion reticulation”, “thermal reticulation” or “percussive reticulation”.
  • such a procedure may be employed in the processes of £he invention to5 reticulate elastom ⁇ do matrix loo. fcaQOtheremb ⁇ dimeiit.teticulatioaigaccorflplialied fl ⁇ ough a plurality of reticulafcon steps. 3h another embodiment, two reticulation steps are used. In, another embodiment, a first combustion re ⁇ culadon is followed by a second combustion reticulation. Xn another embodiment, combustion tetic ⁇ lation is followed by chemical reticulation. Ia another embodiment chemical reticulation is followed by0 combustiottieticulatio-i. IQ another embodimcrii; a fir ⁇ cheimcalreticidatioa is followed by a second chemical reticulation,
  • the ⁇ kstommc matrix can be reticulated to provide an iataeonaected pore structure, 'die pores having m average diameter or other largest transverse dimension of at least about
  • thex ⁇ tic ⁇ lattdela ⁇ merici ⁇ atrix has pores -with average diameter or other largest transverse dimension of at least about 150 ⁇ m.
  • the ⁇ lastomeric matrix cm be reticulated to provide pore ⁇ with an average diameter or other largest transverse dimension of at least about 250 ⁇ m.
  • the elasto ⁇ jetic matrix can be reticulated to provide poxes with an
  • the elast ⁇ meric matrix cm. be reticulated to provide pores "with an average diameter or oikwtex ⁇ ixmNecSBtikas ⁇ on of greater than 250 pm.
  • the elastomeric matrix can be reticulated to provide pares with an average diameter or other largest transverse dimension of at least about 275 ⁇ m. Jn
  • the elastomeric matrix can be reticulated to provide pores with an average diameter or other largest t&nsverse dimension, of greater than about 275 ⁇ m.
  • the slastomoric matrix caate reticulated to provide porea with an average diameter or other largest transverse d ⁇ wnsion of greater than 275 ( an. Jn. s another embodiment.
  • Ih* elastomerie matrix can be reticulated to provide pores with an average diameter ot other largest transverse dimension of at least abotrt 300 ⁇ m.
  • the elastomra ⁇ c matrix can be reticulated to provide pores with an.
  • tho elastomeric matrix can bo reticulated to provide pores with, ano average diameter or other largest transverse dimension of greater than.300 ⁇ m.
  • the ela ⁇ omericr ⁇ atrix can berdicTjlatedto provide pore$ ⁇ vith. «n average diameter or o&er larger tRffi&versedirnens ⁇
  • the elastomeric matrix can be i ⁇ tic ⁇ &ted to provide pores with an averageS diameter ox oth ⁇ l. ⁇ gesttr ⁇ sverse ⁇ -i ⁇
  • tho elastomeric matrix can be reticulated to provide pores with an average diameter or other largest, transverse dimension of not greater man about 800 ⁇ xa.
  • the elastomeric matrix can be reticulated to provide pores with, an average diameter or other largest transverse dimension of not greater than about 700o ⁇ m. In another embodiment, the elastomeric matrix cam be reticulated to provide pores -with an average diameter or other largest transverse dimension of not greater than about 600 ⁇ m.
  • the elastomeric matrix can be reticulated to provide pores "with an average diameter or other largest transverse dimension of not greater thaa about SOO /an-$ fix soother ⁇ mbodiaqst relating to vascadarmalfoim-tdon ⁇ pEcationeandtiie like f &eetoomtocr ⁇ -trix «mfceref ⁇ or other largest transverse dimension of from about 100 /on to about 900 pm.
  • me ekstome ⁇ c matrix csa be reticulated to provide pores with an sverage diameter or other largest
  • the elaatomcrio matrix canb ⁇ reticulated to provide pores with an average diameter or other largest transverse dimetu ⁇ onofftom-iboutlOO / ttntoaboutSOO/ar-.
  • the elastomerio matrix can be reticulated
  • the elastomerie matrix can be reticulated to provide pores with aa average diameter or other largest transverse dimension of from about 150 /Jm to about 600 ⁇ m.
  • the s elastome ⁇ o matrix caa be retioulataj to provide pores mik an average diameter or other largest transverse dimension of ftora about 200 fan to about 500 /an. to.
  • the elastom ⁇ tic matrix can be reticulated to provide pores with an average diameter or other largest transverse dimension of greater than about 250 ⁇ m to about 900 JOB.
  • the clast ⁇ reric matrix can bo articulated to provide pores0 with an average diameter or other largest transverse dimension of greater than about 250 ⁇ m to about 850 ⁇ xn.
  • the clast ⁇ merie matrix can be reticulated to provide pores with an average diameter or other, largest transverse dimension of greater than about 250 ⁇ tn to about SOO jam,
  • the elastomwic matrix can bo reticulated to provide pores with an average diameter or other largest5 transverse dimension of greater than, about 250 ⁇ m to about 700 ⁇ m.
  • the elastomeric matrix can be reticulated to provide pores -with an average diameter or other largest transverse dimension of greater than about 250 ⁇ m.
  • the elastomeric matrix can be reticulated to provide pores with an average diameter OF other largest transverse dimension of from about 275 ⁇ m to0 about 900 ⁇ m
  • the elaatpmcric matrix can be reticulated to providepores with, an average diameter or other largest transverse dimension of from About 275 ⁇ m. to about 850 pan.
  • the elastomeric matrix can be reticulated to provide pores with an average diameter or other largest transverse dimension of fiom about 275 ⁇ ta. to about 800 ⁇ m.
  • the elastomeric matrix can be reticulated to provide pores with an average diameter or other largest transverse dimension of fiom about 275 ⁇ ta. to about 800 ⁇ m.
  • 25 elflstomeric matrix can be reticulated to provide pores -with, an average diameter or other largest transverse dimension of from about 275 ⁇ m to about 700 ⁇ m.
  • the elastomeric matrix can be reticulated to provide pores with an average diameter ox other largest transverse dimension of from about 275 ⁇ m to about 600 pan.
  • the reticulated elastomers matrix may be purified, for example, by - 30 £wlv ⁇ itextiactiori, «1lier before or ailcr reticulation.
  • Any such solvent extraction or other purification process is, in one embodiment, a relatively mild process which is conducted so as to avoid or minimize possible adverse impact on the mechanical or physical properties of the elastom ⁇ ic matrix that may be necessary to fulfill the objectives of mis invention.
  • EX One embodiment employs chemical reticulation, where the- elastomeric matrix is reticulated in att acid baih comprising m inorganic add Another embodiment employs chemical reticulation, where the clastomerfc matrix is reticulated in, a caustic bath comprising an inorgsnio base. Another embodiment employs chemical reticulation at an elevated temperature. Another chemical tcticulatioa embodiment employs solvent, sometimes known as solvent reticulation, where .a volatile solvent that leaves no r eeidue is used in the process.
  • a polycartouatepolyarethaae is solvent reticulated with a solvent selected ftom tetrahydtofiiraii (“THF”), dimethyl aceta ⁇ sjde CDMA.C”), dimethyl sulfoxide (“DMSO”), dimethylf ⁇ ans ⁇ aid ⁇ (“DMF 1 O, N-mefeyl-2- pyrrot ⁇ done, also known as m-pyrol, and their mixtures.
  • THF ftom tetrahydtofiiraii
  • DMSO dimethyl sulfoxide
  • DMF 1 O dimethylf ⁇ ans ⁇ aid ⁇
  • N-mefeyl-2- pyrrot ⁇ done also known as m-pyrol
  • a polycarbonate polyiirethane i$ solvent xeticoteted with N-mcthyl ⁇ -pyrrolidone Ih another smbodiment, a polycarbonate poly ⁇ cthane h chemically raticnl ⁇ -ted wifh a strong bass. In aaotibcr embodknent. thepH of the strong base is fit least about 9. Ih any ofth ⁇ se ch ⁇ mcalttticulafionem ⁇ optionaJly be washed. Ia aay of these chemical icti ⁇ tlation etnbodiineiits, the reticulated foam cau optionally be dried.
  • combustion reticulation may be employed in which a combustible aimospheie, e.g., a mixture of hydrogen aad oxygen, is ignited, e.g., by a spaxk.
  • a combustible aimospheie e.g., a mixture of hydrogen aad oxygen
  • IR mother embodim ⁇ mt 1 comfcv ⁇ mietic ⁇ tion is wndurted in a pressure chamber.
  • the pressure in the pressure chamber is substantially reduced, e.g., to helow about 150-100 milHtorrby evacuation for at least about 2 minutes, before hyd ⁇ 3gan, ⁇ 5 ⁇ j ⁇ ao ⁇ a inixtoreconfigurationiwfiamtwduc ⁇
  • the pressui ⁇ mihDpioss ⁇ rechfflnbcrwsuliSt-oitiallyroduc ⁇ iamo eg., the pressure is ⁇ stantiaHy reduced, ⁇ xmrcac ⁇ ve gas mic ⁇ jtroducedtheuttiepresattit is again substanii ⁇ ia-xu ⁇ lwfc ⁇ hydrogen, oxygen or a fi-dxt «re thereof is introduced.
  • the t ⁇ i ⁇ eratuitj at wHdi reticulation occurs can fee i ⁇ flucnccd by, e.g., the temperature at which the cbamber is ⁇ itrintained and/or by tixo hydrogen/oxygon ratio in the chamber, Jt ⁇ another ejx ⁇ odiment, combustion reticulation is followed by an annealing period.
  • combustion reticulation is followed by an annealing period.
  • the mficulated foam can optionally be washed, ⁇ n any of those combustion redcnlati ⁇ n cmbodimeats, the reticulated fb ⁇ n can optionally he dried
  • the reticulation process is conducted to provide ea, els-jtomeric n ⁇ atnx con €guntion fiivoiing cellular ingrowth end proliferation into the
  • suitable elastomer materials for use in the practice of the present invention i ⁇ one embodiment sufficiently well charaote ⁇ scd, comprise elastomers that have or can be foimulatcd with ⁇ de ⁇ iratol ⁇ mechanical properties described in tiie present specification and have a chemistry iavorab ⁇ e to bioduratOity such that they provide a reasonable ej ⁇ ectatio ⁇ of adequate biodurability.
  • thermoplastic polVHrethanc ojastomeis include polycaibonato polyiiretbaneS f polj ⁇ rpolyurethanesjpolyctherpolym ⁇ h ⁇ c ⁇ polysilo ⁇ polyureflianes, hydrocarbon poly ⁇ refhanss (i.e., those th ⁇ »o ⁇ lastic elastomer polyvrethB ⁇ es formed fiom at least o ⁇ e i ⁇ ocyanate component comprisiag, on the average, about 2 is ⁇ cyanat ⁇ gi ⁇ ups per molecule and at least one hydioxy-termioatcd hydrocarbon oligomer and/or hydrocarbon polymer)* polyursflia
  • thethe ⁇ aoplast'c polyarethane d ⁇ tomcr includes polycarbonate polyurethanes, polyetJter polymethan ⁇ ?, polysiloxans polyureth ⁇ nos, hydrocaiboa polyurethanes, polyurcthama with these mixed
  • the ⁇ noplastic polyur ⁇ thane elastomer includes polycarbonate polywethaneg, polysiloxane polyuwfhaiites, hydrocaibon polyuretnanes, polyurethancs with these mixed soft segments, or mixtures thereof, fa another.cmbodiment, the thermoplastic polyurethan ⁇ daftom ⁇ is apoIycarboti4epolyt-tethan ⁇ orni-x(OTCsthejccof: Ia another embodiment, the thermoplMic polyttretnane elastomer is apolysiloxane poty ⁇ rotha ⁇ o, or mixtures thereoC Xa another embodiment, the thermqplastfe p ⁇ iyr ⁇ sthaiic elastomer is a polysfloxac ⁇ poly ⁇ iethane, or mixtures thereof, jh another embodiment, the thermoplastic polyurctbane elastomer
  • the weight average roolecalar weight of the thermoplastic elastomer is from about 30,000 to about 500,000 Daltons.
  • the weight average molecular weight of the thermoplastic elastomer is from about 50,000 to about 250,000 Dalto ⁇ s.
  • Suitable ⁇ homoplastics fbr practicing the invention can include; polyolcfinic polymers with alternating secondary and quaternary carbons as disclosed by Pinchuk et al. in U-S. Patent No.5,741,331 (and its divisional U.S, Patents Nos.6,102,939 and 6,197,240); block; copolymers having an elast ⁇ meric block, eg,, a polyole& ⁇ , and a the ⁇ noplaatic blcjck, e.g., a styr ⁇ ne, as disclosed by Pinchuk et al.
  • thermoplastic segmented polyetherest ⁇ r thermoplastic polyd ⁇ notbylsiloxa ⁇ e, di-block polystyrene polybutadiene, td-block polystyrene p ⁇ lybutadiene, poly(acryl «ie ofiier sulfonc>- ⁇ oly(aciyl carbonate) block copolymers, di-block copolymers of polybutadiene and polyisoprenc, copolymers of ethylene visyl acetate (EVA), segmented block co-polystyrenc polyethylene oxide, di- block co-polystyrene polyethylene oxide, and tri-block co-polystyrcne polyeuiylene oxide, e.g., aa disclosed by Penna ⁇ i in U-S.
  • EVA ethylene visyl acetate
  • Patent Application Publication No. 2003/0208259 Al (particularly, see paragraph [00353 therein); andpo ⁇ yurethanes with mixed soft segments comprising poIysiJoxane together with a polyethe ⁇ sod/or a polycarbonate co ⁇ on ⁇ nt, as disclosed by Meqs et aL in U.S. Patent No.6,313,254; and those polyuret ⁇ aaes disclosed by DiDome ⁇ ico et al in U.S. Patent Nos, 6,149, ⁇ 578, 6,111,052 and 5,986,034. Howler, & cweful teadrog of Brady '550 indicates that the
  • IBIT 1 polyeth ⁇ r or polycarbonate polyurethanes having isocyanurate linkages disclosed therein are not suitable because, inter alia, they are not thennoplastic.
  • an optional therapeutic agent may be loaded into the appropriate blwk of other elastomers ⁇ acd in ths practice of the rave ⁇ iioii-
  • Som ⁇ commerdaUy-avfliiablc theimoplaatio elastomers suitable for use i ⁇ practicing the present invention include the line ofpolycarbonaio polyuieQiaaes supplied under the trademark BIONATB® by The Polymer Teehfid ⁇ gy Group l ⁇ c. (Berkeley, CA).
  • the veryweU ⁇ fca ⁇ urter-zed grades of polycarbonate polyurethane polymer BIONATE® 80A, 55 and 90 are soluble in THF, processable, reportedly have ' good mechanical properties, lack cytotoxicity, lack mutagenicity, lack carcinogenicity and are non-hemolytic.
  • Another co ⁇ unerciaUy-avs ⁇ able elastomer suitable for use in practicing the present invention is the CHRONOFLEX® C U ⁇ e of bi ⁇ dwable medical grade polycarbonate aromatic polyurethane tij ⁇ noplastic elastomers available fiom Cs- ⁇ oTecliI] ⁇ tTO ⁇ oaal,lDc. (Woburn » MA).
  • thermoplastic polyuie ⁇ iane elastomers in particular (be 2363 series products and more particularly those products designated SlA and 8SA, supplied by Th* ⁇ w Chemical Company ⁇ Midland, Mich.).
  • SlA and 8SA supplied by Th* ⁇ w Chemical Company ⁇ Midland, Mich.
  • Sacrificial Molding Process Tbc following sacrificial taol ⁇ g process may be performed using any of the thermoplastic elastomers described above as ⁇ e fl ⁇ wable. polymeric material or as a component ti ⁇ ereof.
  • Hie flowablo polyt ⁇ aio material in the sacrificial molding process comprises a polycarbonate pory ⁇ rethane.
  • Keferrf ⁇ g now to the sacrificial molding process for preparing a reticulated.
  • biodurable elastome ⁇ c matrix illustrated i ⁇ Figure 9 the process comprises aa initial step 70 of f&bricaring a sacrificial mold or substrate permeated with externally communicating interconnecting interior passageways, which interior passageways are shaped, configured and dimensioned to define or mold the elastomeric matrix with a desired reticulated microstructural configuration.
  • the substrate or sacrificial mold can comprise a plurality of Bolid or hollow beads or particles agglomerated, or interconnected one with, smother at multiple points on each, particle in the manner of a network.
  • &e mold may comprise a plurality of waxy particles compressed together so thai each particle contacts its
  • the particles are symmetrical, but they may have any suitable shape, e.g., an isotropioally symiaeirical shape, fox example, dodecBhedral, icosahedral or spherical ⁇ one embodiment, before compaction, the particles arc spherical, each with a diameter of from about 0,5 mm to0 about 6 mm.
  • the mold may comprise a pluraJity of particles comprisiiig a material having water solubility, for example, an inorganic salt such as sodium chloride or calcium chloride, or a starch such as com, potato, wheat, tapioca, manioc or rice starch.
  • a pluraJity of particles comprisiiig a material having water solubility, for example, an inorganic salt such as sodium chloride or calcium chloride, or a starch such as com, potato, wheat, tapioca, manioc or rice starch.
  • the starch can. be obtained fiom, e.g., com or maize, potatoes, wheat, tapioca,s manioc and/or rice, by methods known to flbiose in the art Ia one embodiment the starch, is a mixture of starches. In another embodiment the starch contains from about 99 wt% to about 70 wt.% amylopeetin. In another embodiment the starch contains sbottt 80 wt% amylopectm and about 20 wt.% amylose.
  • Suitable granular starches include the modified rice starches RBMYLINE pk (available ftomAB ⁇ lL ⁇ Hidb ⁇ £g,Malmc>, Sweden) and0 MIKROLYS 54 (amiable from Lyckeby StarbelseAB, Sweden), the PHASMOEL line of starches and modified starches available from the Cerestar Food & Eha ⁇ na division of CargOl (Cedar Rapids, IA), the wheat st ⁇ rch ABSASTA&CH (ABR.
  • RBMYLINE pk available ftomAB ⁇ lL ⁇ Hidb ⁇ £g,Malmc>, Sweden
  • MIKROLYS 54 amiable from Lyckeby StarbelseAB, Sweden
  • the PHASMOEL line of starches and modified starches available from the Cerestar Food & Eha ⁇ na division of CargOl (Cedar Rapids, IA), the wheat st ⁇ rch ABSASTA&CH (ABR.
  • 2$ size ofthe starch can be acM ⁇ v ⁇ by methoa ⁇ known to those in the art
  • ft* staich particles can be sieved to thfc desired size
  • water can be ased t ⁇ agj$oioerat ⁇ snail starch
  • particles into larger particles or a binder can be used to agglomerate small starch particles into larger particles, e.g., as disclosed in U.S. Patent No.5,726,161-
  • a ⁇ aqueous solution or suspension of starch particles can be placed into the
  • pores of aretic ⁇ latcd foam structure (a "positive"), e,g., a nonmedical grade commercial feam formed fiompoly ⁇ waia ⁇ e, the st ⁇ icacanbegdfltini. ⁇ sample can be dried under reduced pressure and/or baked toicanova water, and the foam removed by dissolving it with a solvent, eg., THF for a poly ⁇ rottiane foam, that is also & nonsolvcnt for the starch, thereby yielding a starch assembly (a "negative") that can be 35 readily ⁇ bricated into starch particles having an. average diameter about that of the pore
  • a solvent eg., THF for a poly ⁇ rottiane foam
  • the particles may bo interconnected using heat and/or pressure, e.g., by sintering or fusing.
  • heat and/or pressure e.g., by sintering or fusing.
  • the particles aw mtetc ⁇ nnected by sintering, by fusing, by using an adhesive, by the application of reduced pressure, or by any combinafionjl--jere ⁇ )£ Ih
  • waxy particles are fused together by raising their temperature.
  • starch ⁇ artidc& are fused together by rajs ⁇ igthdrteirape ⁇ -t ⁇ re.
  • inorganic salt particles are fused together by exposing them to moisture, eg,, 90% relative humidity.
  • resilient particles may be employed providedihat they can be elated f ⁇ xtn the matrix, for example, by elevating their temperature to liquefy them, by dissolving them with a. solvent or solvent blend, or by elevating their temperature wad dissolving them,
  • the mold has a dgmficaot threo-dimensional extent -with multiple particles extending in each dimension.
  • the polymeric material is wntamcdwithra the interstices between the interconnected particles. 3n ano&er embodiment, the polymeric material fills the interstices between, the interconnected particles.
  • lhe particles comprise a material having a melting point at least 5 0 C lower than the softening temperature of the polymer that is contained within the interstices.
  • me particles comprise ftn ⁇ point at least 1O 0 C lower than the softening temperature of the polymer that U contained within the interstices.
  • the particles comprise a material having a melting point at least 20*C lower than the softening temperature of the polymer that is contained within the interstices.
  • the particles comprise a material having a melting point at least 5 0 C lower man the Vicat softening temperature of the polymer that is contained wré the interstices.
  • flie particles comprise a material having a melting point at least 1O 0 C lower than the Vicat softening temperature of the polymer that is contained within the interstices.
  • the particles comprise a material having a melting point at least 20 0 C lower than title Vicat softening temperature of the polymer that is co ⁇ taraed within the
  • the particles ofih ⁇ moW ⁇ a ⁇ .y be a hydrocarbon wax
  • Ia another etnbodiracni the removed particle material can, be recovered after melting and reformed into particles ⁇ )r reuse.
  • the particles comprise an inorganic salt which m $ y be removed by dissolving the salt in water
  • Ih another embodimcnt the particles cojotpris ⁇ a starch which may be removed by dissolving the starch itt a solvent for the starch.
  • H another embodimc ⁇ ⁇ particles comprise a starch which may be removed by dissolving the starch in water.
  • the particles comprise a starch which may be removed by dissolving the starch in an aqueous base, such as aqueous NaOH.
  • an aqueous base such as aqueous NaOH.
  • the particles by dissolving tine starch i ⁇ about US M aqueous KaOH, in another embodiment about 2.5-3 M NaOH, in another embodiment about 2.5 M KaOH.
  • the aqueous base ftrther c ⁇ r ⁇ prises sodium.
  • the particles • comprise a starch which maybe removed by the enzymatic action of an enzyme, as 3movmtotlioso inthe art P ⁇ rctsrnpie, ⁇ c ; en7yni ⁇ canbe &-. alpha'aniyla8 ⁇ (E.C.
  • Suitable alpha-amylasss include the HKMAMYX 120L S, L and LS types (Novo Nordisk Bioiadustries S-A., Nantetre, Vtaac ⁇ ), SV 1 BZVME AA, end AAL (G ⁇ neacor, Delft* Netherlands), aad NE ⁇ LVANASB and G-ZYME G995 (Rhodis, Che ⁇ bire, UK); suitable pT ⁇ U ⁇ lanasea include AMBAZYME P20 (Rhodia), PROMOZYMB 200 L (Novo Nordisk), end OPTlMAX L300 (Oensncor); and suitable amylo ⁇ .ucosidases include OFHDEX L300 and OP ⁇ MAX 752S ( ⁇ ta&wQ ⁇ ), AMG 30OL (Novo Nordiafc), aad other enzymes cited nt coli ⁇ nn 5, Jines 7-19 of U.S. Patent No.6,569,653
  • the substrate may bo given an anaphiphilic coating to induce hydrophilicity in tix ⁇ mn&ce ofthc elastomer as it sets.
  • anaphiphilic coating for example hydiOcarbon, wax particles, mfyte coated with a detergent, lecithin, fimctiona ⁇ zed silicones, ortho l ⁇ ks, ⁇ n
  • the snbstrate comprises two phases: a substrate material phase and a spatial phase.
  • the substrate material phase comprises a threo-dimenaor-ally extending network of substrate particles, continuously interconnecting one with, the next, interspersed with a three-d ⁇ nerMonally extending network of interstitial space? also
  • the JEtowabl ⁇ ' po ⁇ ymeric material maybe a polymer so ⁇ ti ⁇ n, emulsion, noicio ⁇ ndsioQ, suspension, dispersion, a liquid polymer, or a polymerm ⁇ lt
  • the flowable polymeric material can comprise a solution of the polymer in a volatile organic solvent, for example THF.
  • the polymeric material can comprise a th ⁇ moplastic elastomer and the flowable polymeric material can comprise a solution of that meraoplastic elastomer.
  • the polymeric material can comprise a biodurabl ⁇ themioplastic elastomer, as described herein, and the flowable polymeric material can comprise a solution of fiiatbiodurable thermoplastic elastomer, ⁇ a another en-boduwa ⁇ k thopor ⁇ ericr ⁇ atorM mermoplflstic elastomer and the ft ⁇ wable polymeric material can comprise a solution of that solvent-soluble Modutable thermoplastic elastomer.
  • the solvent can men be removed or allowed to evaporate to solidify me polymeric material.
  • Suitable elastomers include the BIONATE® line of polyorethane elastomers. Others ate described herein or willfce known or apparent to those skilled in fiw art
  • solvents are biocompatible and sufficiently volatile to be tead-fyrranoved.
  • One suitable solvent depending, of course, upon the solubility of the polymer, k THF.
  • Other suitable solvents include DMAC, PMF, DMSO and N ⁇ ncthyi- 2- ⁇ jtetolido ⁇
  • solvent mixtures can be used, e.g, mixtures of at least two of 1 XHF, DMAC 1 DMP, DMSO and N-me(hyl-2-pyirQli «ion ⁇ r. Additional suitable solvents -will be 3cnown to those sldlied in the art
  • the eaorifici i ⁇ moldmgprcwessfiDrther comprises 8olidi-5dngthepolymenc material, step 740, which may be effected in any desired manner, for example, by solvent exchange or by removing me solvent by evaporation, optionally assisted by vacuum and/or heating to a temperature below Ilie ⁇ fte ⁇ ngten ⁇ eratares of the polymer or of the substrate material. If sufficiently ⁇ volatile, the solvent may be allowed to evaporate off, Cg ⁇ , overnight The product resulting fi ⁇ m step 74Oi 8 a solid oomplex comprising interspersed polymer material and substrate.
  • the matrix comprises int ⁇ rcowjectmg cells each defined by one of the removed particles. Most or many of the cdla are opea-watted to provide matrix 7S0with good fluid permeability, ⁇ n another embodiment, matrix 780 maybe reticulated to provide a reticulated matrix. In another embodiment, for endovasen-ar applications* the awtrix is folly reticulated -with few, if any residua! cell walls. .
  • the structure of elastome ⁇ r ⁇ matrix ioothat is produced without the need to employ a separate reticulation process step is, in one embodiment, a "reticalated 1 * or an "at least partially reticulated" one, Le., at least about 50% of the cell waits are absent
  • the structure of elastomeric matrix ioothat is produced without the need to employ a separate reticulation process step is a "farmer reticulated" one, i.e., at least about 65% of the cell walls are absent
  • the ⁇ trvctute of elastomeric matrix ioo mat is produced without the need to employ a separata reticulation process step is a "sutistanuaUy reticulated" one, Le., at least about $0% of the cell walls are absent
  • the structure of elastomeric matrix iocthat is produced without the
  • Exemplary annealing conditions include heating too elastomeric matrix to a temperature of from about 35°C to about 150 0 C and maintaining the ⁇ lastomeric matrix in mat te ⁇ erature range for about 2 hours to about 24 hours.
  • the invention also provides what may, for simplicity's sake and without limitation, be ftumght of as a so-called "double lost wax puocess" for producing a reticulated biodurable et ⁇ stanieric matrix ioo.
  • a template of the desired product shape is obtained aud coated with, a first coating.
  • the ten-plate is removed and the coating is then coated -with a second coating of the final polymer material. Whet, the first coating is removed, fho desired product made fto ⁇ l the final polymer material icmaina.
  • Ike fii ⁇ coating can t ⁇ fomod from a starch, such as those previously described, by depositing an aqueous starch solution or suspension onto or into the template ⁇ pwf ⁇ immg R starch, gslatinization step, ⁇ s previously described* optioi ⁇ aUy followed by removal of the water.
  • a desirable template would bo a commercial reticulated ⁇ osslinked foam, e.g., a noa-biodmablc polyurethane.
  • crossliaksd foam is directly coated, e.g., with a flowab ⁇ e thermoplastic ef ⁇ st ⁇ mer such as one from the B ⁇ ONATB® or CHRONOFLEX ⁇ product liae ⁇ described above, the crossli ⁇ fosd reticulated t ⁇ Q-plate, being crc ⁇ Unked, cannot be easily removed. If a strong acidic ot caustic extraction of the crosslir&ed foam template were to be attempted, thereby destructively converting it into a solution, such extraction could also dissolve or destroy the thermoplastic elastomer costing.
  • a foam template e.g., a reticulated poly ⁇ rethane foam that may be noa-biodurable
  • a flowsble resistant material e.g., a solution cojooprising a materiel resistant to attack by a strong hot acid or base to be employed for dissolution of the foam template or a liquid form of the resistant material.
  • me resistant material of the first coating can comprise a solvent-soluble but add- or base- insohiblc th ⁇ rmoplastic.polymer or wax.
  • the foam template is removed, e.g., by extraction wi ⁇ k hot acid or base, leaving a &hell-lD» t»s ⁇ istant material fbimwhi ⁇ coated with a flowable polymeric material such as flowablc form of the desired solid phase i20,e.g- » a solution of biodurablefiolyurethaiie in a solvent, as the second coating.
  • a flowable polymeric material such as flowablc form of the desired solid phase i20,e.g- » a solution of biodurablefiolyurethaiie in a solvent, as the second coating.
  • Removal of the resistant first coating material e.g., by solvent-extracting, raclting-oiit'or sublxmiflg-away the wax, yields a reticulated b ⁇ odwable polywethane elagtomeric ro ⁇ trix.
  • the following double lost wax process may bo performed using any of the the ⁇ aoplastic elastomers described above as the flowable elastomeric polymeric material or a$ a component thereof Ia one embodiment, fh ⁇ flowable elastomeric polymeric material in the double lost wax process comprises a polycarbonate polyuretlume.
  • Qu illustrated double lost wax process comprises an initial ⁇ 900of coatmgareticu-Jrtcd&amtci ⁇ lfltofbrmed, for example, of thepolyureftane CREST FOAM ** grade S-20 (available fiom Crest Foam, Iwx, Moonachie, NJ), with a solvent-soluble, readily meltable or subliaiablc thennoplastio or wax, such as polystyrene, polyvinyl chloride, paraffin wax or the like, applied fiona fhe melt or solution of the thermoplastic or wax.
  • a cross-sectional view o£ e.g., a cylindrical strut section «o of tlie coated foam product of step 9oo comprises a ring 940 of wax around a core ⁇ t ⁇ f the foam template
  • step 9sa aoy solvent is removed, e.g., by drying, sad a surface of the polj ⁇ ireQime ooi ⁇ ateiial of the coated i ⁇ ciilaled foam template is «j ⁇ ose4 e,g., ' by cutting.
  • the po ⁇ varethan ⁇ foam template is r ⁇ noved, e.g., by dissolving it using hot acid or base, to yield & wax casting of the teticulated foam core.
  • step 1020 comprises coating the wax casting with a ftawablc elastomedc polymeric materia-- such as a solution or melt of a biodura ⁇ le polyurethane elastomer, e.g., one of the grades supplied under the trademarks CHRONOELEX ⁇ and BIONATBS).
  • a cross-sectional -view of , e.g., a cylindrical strut sectioD 10 ⁇ 0 of me elastomet ' C ⁇ ated wax casting product of step 1030 comprises a biodurabl ⁇ elastomer ⁇ ng io «o around a core co ⁇ tp ⁇ mg wax ring 940.
  • the flowable el ⁇ stomeric polymeric material is them solidified by, e.g., removing the solvent of a solution or cooling a polymer melt
  • step loso comprises exposing tbe thermoplastic or wax, eg., t>y cutti ⁇ g the elwtemeiic polymer matrix.
  • thermoplastic or wax is removed, e.g., fey melting, dissolving or ffublimi ⁇ g-away the casting, to yield an elastome ⁇ c polymer material matrix shown a otOBS-seot-o ⁇ al -view of, ⁇ .g., a cylindrical stmt section, as ring 1120.
  • a. biodurable reticul ⁇ bed elfigtometio matrix of the invention can b ⁇ made by lyophjf ⁇ ing a flowabb polymeric material.
  • the polymeric material comprises a solution of a solvent-soluble bio ⁇ rab ⁇ c elastomer in a solvent
  • the flowabks polymeric material is subjected to a lyopMKzatioa process comprising soMfying the flowabfe polymeric material to form a solid, ⁇ .g., by cooling a solution, thon u ⁇ moviag fbe non ⁇ otyr ⁇ eric material, eg., by subliming the solvent fiom the solid ⁇ idtf reduced pressure, to provide an at least partially reticulated elastomeric matrix.
  • the density oftt ⁇ at least partially reticulated dastomciic matrix is less than me density of the starting polymeric material.
  • a solution of a biodurable elastomer in a solvent is substantially, but not necessarily completely, solidified, then the solvent is sublimed fiom that material to pi ⁇ vide an at least partially reticulaied elastomeric matrix.
  • the temperature to whicb the solution is cooled is below the freezing temperature of the solution
  • the temperature to which ft ⁇ ⁇ oMonis cooled is above the apparent .glass transition temperature of the solid and below the fre ⁇ i ⁇ ng temperature of ⁇ esoMon.
  • a polymer solution separates in a controlled manner into either two distb ⁇ t phases, e.g., one phase, Le., the solven ⁇ being continuous and the other phase being dispersed in flu? continuous phase, or into two bicontinuous phases, Ih each Case, subsequent removal of the solvent phase results in a porous structure with a range or distribution of pore sizes. These pores a» usually ⁇ rteroomxected. Their shape, size and orientation depend upon the properties of the solution and the lyopbijjzation. processing conditions in conventional ways.
  • & lyophilization product has a range of pore sizes with dimensions that can be changed by altering, eg., the freezing temperature, freezing rate, nuctearion density, polymer concentration, polymer molecular weight, and the type of ⁇ olvent(s) in ways known to those in the art,
  • So ⁇ commerci-uly-available themoplasfic elastomers statable for use in practicing lyophilization for the present invention include but me not limited to those discussed above in connection wfth obtaining re ⁇ cuJsted elastomeric matrices by the
  • Morwv ⁇ r in anoQiwr embodiment polyurethan ⁇ tfaormoplastic elastomers having mixed soft segments comprising poly ⁇ iloxan ⁇ together wiib a polyether and/or a polycarbonate w ⁇ ap ⁇ nent, as disclosed by Mcijs et al. in U.S. Pateat No. 6,313,254, caab ⁇ used. Solvents for use in practicing lyophj ⁇ izatioa.
  • the amount of polymer m the solution is Jrom about 0.5% to about 30% of the solution by weight in one embodiment, depending . upon the solubility of the polymer in the solvent and the final desired properties of the clastomerio reticulated matrix.
  • 3k mother embodim ⁇ at ( 1iio aDiovmtofpolym ⁇ ri ⁇ fire solution, is from about 0.5% to about 15% of the solution by weight
  • additives may be present in the polyr ⁇ er ⁇ olvent solution, e.g., a buffer, Ia one embodiment, the additive does not react with the polymer or the solvent Ea another embodiment, the additive is a solid material that promotes tissue regeneration oriegrowth, a buffer, a reinforciDg material, a porosity modifier or a phannaceutically- active agent
  • the polymer solution can comprise various inserts iacoipoxated -with the solution, sa ⁇ h as films, pistes, foams, scrims, woven, oonwoven, knitted or braided textile structures, or implants that have surfaces that are not smooth.
  • sa ⁇ h as films, pistes, foams, scrims, woven, oonwoven, knitted or braided textile structures, or implants that have surfaces that are not smooth.
  • these inserts comprise at least one bi ⁇ c ⁇ u ⁇ atible material and may have anon- absorbability and/or absorbability aspect
  • ft function o ⁇ e.g., tnc solution thermodynamics, freezing rate and temperature to which the solution is cooled, polymer concentration in the solution and type of nuclcatio ⁇ , e.g., homogeneous or heterogeneous.
  • the ly ⁇ philizer for the polymer solution is cooled to about -80 0 C.
  • the lyophilizcr for the polymer solution is cooled to about -7O 0 C.
  • Hie lycjpailiz ⁇ r for the polymer solution is cooled to about -40 0 C
  • the ryopbj ⁇ izer comprises & shelf onto which the polymer solution is placed snd the shelf is cooled to about -8O 4 C- In aaotheremb ⁇ >dim«it, the shelfja cooled to about -70 0 C Ih another embodiment, the shelf is cooled to about -40 0 C, The rate of cooling to fieezo the
  • -61- polymer solution can be from about 0-2°C/fl ⁇ i to about 2.5*C ⁇ nin.
  • lhe polymer solution is placed into a mold and the mold is placed into the lyopMlizer. Hie walls of the mold undergo cooling in the lyophilizer, e.g., as they contact the fitw- ⁇ -drycr shelf.
  • the temperata W of the lyopMlizeri ⁇ reduced a* the dearedwr ⁇ attained.
  • the mold is placed onto & cooled she ⁇ £ tins heat transfer front moves upwards Scorn, the lyophiliz ⁇ r shelf through the mold -wail into the polymer solution, Th?
  • fhc solution can phase separate into two di ⁇ tii-Ct phases or Into two hicontmttous phases, as discussed previously.
  • the morphology of the phase separated system is locked into place during the fieest ⁇ g step of the lyophilizatio ⁇ process.
  • the creation of pores is initiated by the sub ⁇ imatioa of the solvent upon exposing the frozen material to reduced pressure
  • a higher conoentrst ⁇ on of the polymer to the solution higher viscosity (attributable to higher concentration or higher molecular -weight of the polymer) or higher cooling rate ara thought to lead to smaller pore sizes while tower concentration of the polymer in the solution, lower viscosity (attributable to lower concentration or lower molecular weight of the polymer) or slower cooling rate are thought to lead to larger pore sizes in the lyophiHzed products.
  • the internal surfaces of porca 200 may he "eMopotcosly coated", ie.» coated or treated to impart to those surfaces a degree of a dedicddiararteristic, e.g., hydrophilicity.
  • the coating or treating medium can have additional capacity to transport ox bond to active ingredients that can then he preferentially delivered to por ⁇ 3200.
  • this coating medium or treatment can be used facilitate covalent bonding of materials to the
  • the coating comprises a biodegradable polymer and an. inorganic ccmipouentj.sncb, as hydroxy ⁇ patite
  • Kydrophilic treatments may b ⁇ effected by c-waiical or xadia ⁇ o ⁇ treatments on the fabricated reticulated elast ⁇ meric matrix ⁇ m, by exposing -the elastomer to a hydrophii ⁇ o, ⁇ ,g., aqueous, environment during elastomer setting, or by other means known, to those skilled in Hie art.
  • ono or more coatings may be applied endoporotr ⁇ ly by contacting . with 8 film-fo ⁇ rang biocompatible polymer either in a liquid coating solution, or in a melt - state under conditions suitable to allow the formation of a biocompatible polymer film.
  • 8 film-fo ⁇ rang biocompatible polymer either in a liquid coating solution, or in a melt - state under conditions suitable to allow the formation of a biocompatible polymer film.
  • the bonding strength is such tfcat the polymer f ⁇ c ⁇ does not crack or dislodge during handling or deployment of reticulated elasto ⁇ wric matrix loo.
  • Suitable biocompatible polymers include poJyamides, polyolcfins (?.g., polypropylene, polyethylene), nonabsorbable polyesters (e.&, polyethylene twephthalate), andb ⁇ oabsoibabl ⁇ aliphatic polyesters (e.g., homopolymera aad copolymer of lactic acid.
  • biocompatible polymers include £Im-focmng bioabsorbable poiymcr.; these include aliphatic polyesters, poly(smmo adds), copoly( ⁇ mer-e3tets), polyalkylcn ⁇ s oxalates, polyamides, poly(immocarbonates), polyorthoestois, polyoxacsters i ⁇ cluding polyoxa ⁇ sters containing amido groups, polyamidocstmrs, polyanbydrides, polypho ⁇ hazenes, ttomolecules and blend* -thereof.
  • polyesters include polymers and copolytncr ⁇ of lactide (which, includes lactic acid d-, 1- and meso lactide), c- ⁇ aptoUictonc, ⁇ ycolide (including glycolic acid), hydroxybutyrate, hydroxyvalerate, para-d ⁇ oxanone, tdme ⁇ iylcnecarbo-iatc (and its a ⁇ kyl de ⁇ vatives), l,4-dioxepan.-2-on ⁇ , l ⁇ -dioxe ⁇ a ⁇ -2- one, ⁇ . ⁇ -dimethyl-l ⁇ - ⁇ oxan-S-OR ⁇ and blends thereof
  • Biocompatible polyn ⁇ xs farmer i ⁇ cl ⁇ de film-fo ⁇ ning biodurable polymers vAih relatively low chronic tissue response such as polyurcthaucs, silicones, poly(metli)aciylates, polyesters, polyalkyl oxides (e.g., polyethylene oxide), polyvinyl alcohols, ' polyctbylcne glycols and polyvinylpyrrolidone, as well as hydrogcls, such as those fomwd ftom. crossli ⁇ ked polyvinyl pynolidinoae and polyesters, Other polymers, of course, can also be used as the biocompatible polymer provided that they can be
  • polymers and copolymers include polyolefins, polyisobutylene and ethyleno- ⁇ -olefi-i copolymers; acryEcpolyiner ⁇ (mehidjng m ⁇ thacrylatas) and copolymers; vinyl halid ⁇ polymers and copolymer such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ethe ⁇ polyvinyUdene halides such as po ⁇ yvinylidene fluoride and potyvinylidene chloride; polyactylonit ⁇ lc; polyvinyl Sartones; polyvinyl aroniatics such 88 polystyrene; polyvinyl esters such as polyvinyl septate; copolymers of vinyl monomers 'with each other and with, ⁇ -okfins, such as etheyfa ⁇ e-me ⁇ xyl metbacrylato cop
  • n is an integer from about 4 to about 13; x i ⁇ a& integer from about 4 to about 12; and y is an integer from about 4 to about 16. It is, of coarse; to be understood tbat the listings of materials above are illustrative trat not limiting.
  • ⁇ us devices made fbox ⁇ reticulated elastomeric matrix ⁇ generally axs coated by simple dip or spray coating-w ⁇ th a polymer, optionally comprisbig a phannaceutically- active agent, such as ⁇ therapeutic agent or drug, Ih one embodiment ⁇ the coating is a solution and the polymer content in the coating solution is from about 1% to about 40% by weight Ia another er ⁇ bo ⁇ dtoeat; the polymer content in the coating sohition is ftom about VA to about 20% by weight. In another ⁇ jtdbodaaent, -fitve polymer content in the coating solution is fmm about 1% to about 10% by weight.
  • the solvent or solvent blend for the coating solution is chosen with consideration given to, inter ⁇ li ⁇ , the proper balancing thu viscosity, depositicm. level of the polymer, wetting rate and evaporation rate of the solvent to properly coat solid phase i20, as known to those in the art.
  • the solvent is chosen such the polymer is soluble in the solvent.
  • the solvent is substantially completely removed from the coating.
  • Bi another r ⁇ nfcrctiment the solvent is non-toxic, non-carcinogenic and environmentally benign. Mixed solvent systems can bo advantageous for controlling the viscosity and evaporation rates, Ih all oases, tho solvent should not react with the coating
  • -64- polymer- Solvents include by are not limited to: acetone, N-methylpyrrolidonn ("NMP"), DMSO, tohaofs, methylene chloride, cMoioform, U ⁇ trichlorocthsne C 1 XCE").
  • NMP N-methylpyrrolidonn
  • DMSO dimethylpyrrolidonn
  • tohaofs methylene chloride
  • cMoioform U ⁇ trichlorocthsne C 1 XCE”
  • the film-fo ⁇ ning coating polymer i$ a thermoplastic polymer that is melted, enters the pores 20Co£the elast ⁇ meric matrix too and, upon cooling ot solidifying, forms a coating on at least 3 portion of the solid material 120 of the elastomeric matrix 100.
  • the processing temperature of the thermoplastic coating polymer in it? melted fb ⁇ n is above about 6O 0 C
  • the processing tempcisstuie of the thermoplastic coating polymer in its -melted form is above about 9Q°C.
  • tiic processing temperature of the the ⁇ noplastiD coating polymer in its melted fbmx is above about 120'C.
  • some or att of the poxes 200of ⁇ lastomcric matrix 100 are coated ox filled with a cellular ⁇ ngrowth promoter.
  • the promoter can be foamed,
  • the promoter can b « present as a fiitm.
  • the promoter can be a biodegradable tnatwial to promote cellular invasion ofcl ⁇ omcric matrix 100 /rt vfw.
  • Promoters include naturally occurring materials that can be enzymatically degraded in the hmnan body or are hydrolytically unstable in the human, body, such as fibrin, fibrinogen, collagen, elastin, hyaluronic acid and absorbable biocompatible polysaccharides, such as cbitosan, starch, f ⁇ tty adds (and esters thereof), glucosc ⁇ glycaijs aid hyaliirom ⁇
  • the pore surface of elast ⁇ meric roatr ⁇ 100 is coated or impregnated, as described in the previous section but substituting the promoter for the biocompatible polymer or adding the promoter to the bicscompatible polymer; to encourage cellular ingrowth and prolifcratiott.
  • the coatingor-mpregrmtingprocc ⁇ is co ensure that the product "composite elast ⁇ m ⁇ do implantable device",, i.e., a ieticulated elastomeric ⁇ natrix and & coating, as used cerei ⁇ , ictains sufGcient lesiJiency after compression, such that it can be delivery-device delivered, e.g., catheter, syringe or endoscope delivered.
  • Collages* may be infiltrated by forcing, e.g., -with pressure, an aqueous collagen, shiny, suspension or solution into the poxes of an elastomeric matrix.
  • the collagen nr ⁇ y be Type I, ⁇ or IH or mixtures thereof. 3a one embodiment, the collagen type comprises at least 90% collagen ⁇ . Tie co ⁇ cmtotionofcollagm is &om about 0.3% to about 2.0% by weight and the pH of the slimy, suspension or eolation Is adjusted to be from about; 2.6 to about 5,0 at the time of tyophiliza ⁇ on.
  • collagen may be infiltrated by dipping an elastomeric matrix into a collagen slurry.
  • iw composite slastomcrio ' ioiplantablc device caoMve a void phase 140J- ⁇ is sKghtly reduced in volume.
  • the composite dastowteric implantable device retains good IMd permeability and s ⁇ Sews ⁇ t porosity for ingrowth and prol ⁇ fcmtba of fibroblasts or other cells.
  • Coated Implantable Devices Itx some ⁇ plications/a device made from elastom ⁇ ric matrix 100 can have a coated or fused surface in order to present a smaller outermost surface area, because the internal surface area of pores below the surface is no longer accessible. Without being bound by anyparticulax theory, it is thought that tins decreased surface area provides mors predictable and easier delivery and transport through long tortuous channels inside delivery-devices end transport through long tortuous channels inside delivery-devices introduced by percutaneous, n-jnimEUy-mvasive procedures for treatment of vascular malfbrmattoiis, such as aneurysms, axt ⁇ rio venous malfi ⁇ ictions, arterial embolizations or ⁇ other vascular ab ⁇ otrnaJities.
  • vascular malfbrmattoiis such as aneurysms, axt ⁇ rio venous malfi ⁇ ictions, arterial embolizations or ⁇ other vascular ab ⁇
  • tins increased surface area and tli ⁇ hardtiesg of elastoai ⁇ c matrix 10 ° is thought, without being bound by any particular theory, to provoke f ⁇ teari ⁇ wW ⁇ i8io ⁇ yx ⁇ cmse, flCiti ⁇ atetb « onset ofa ⁇ ag ⁇ Mo ⁇ . cascade, provofce intimal proliferation, stjmulaio endothelial cell migration and early onset of restenosis.
  • Surface coating or fusion alters the "porosity of ttw surface", i.e,, at least partially reduces the percentage of pores open to tfee surface, or, in the limit, completely closes-ofythe pores of a coated or fused surface, ie,, that surface is nonporous because it tes substai ⁇ atty no pores remai- ⁇
  • surface coating or fusion still allots ⁇ xe internal interconnected porous structuro of etastomed ⁇ matrix ioo to remain open internally and on other non-coated or non-fused surfaces; e.g., the portion of a coated o* fused pore not at the surface remains interconnected to other pores, end those temainuig open surfaces can foster cellular ingrowth and proliferation.
  • a coated and nnco&ted surface are at an oblique angle to each other.
  • a coated and tmcoaled surface arc adjacent Ik another eiribodiment, a coated and n ⁇ coated gurfkce are nox-adjacent
  • a coated and untreated surface are in contact with each other. Ih another embodiment, a coated and uncoated surface are not in contact with each other.
  • one or more surfaces .of an. implantable device made from reticulated elastomeric matrix ItW may be coated, fused or melted to improve its attachment efficiency to attaching means, e.g., anchors or SUtUfOS 1 go that the attaching means does not tear-through or pull-out from the implantable device.
  • j ⁇ isioa and/ox selective axeltt ⁇ g of the outer ky «r of elast ⁇ meric matrix ⁇ m s can be brought about in several different ways, ⁇ a one embodiment, a knife or a blade used to cut & block of elastomeric matrix MO into sizes and shapes for making ⁇ t ⁇ al implantable devices can be heated to an elevated temperature, for example, as described in Example i3. Ih another embodiment, a device of desired shape and size is cut front a larger block of elastomeric matrix ioo by using a laser cutting device and, in the process,0 the surfaces that con ⁇ c into contact w ⁇ tfcthe laser beam are rased.
  • a cold laser cutting device is used to cut a device of desired shape and size.
  • aleatedmoldcaabotisedto impart the desired size and stape to the device by the process of heat compression,
  • a slightly oversized elastomerie •matrix KM) cut from a larger block, can be placed into a heated mold.
  • the mold is closedS over the cut piece to reduce its overall dimensions to the desired size and shape and fuse those sw&ces ia contact with &e heated mold, fox example,, as described to.
  • the processing tcmp ⁇ ratutc for shaping and sizing is in excess of about 130"C. fa. another e ⁇ obod-mcnt, the layers) a ⁇ d/or portions of the outermost surfe.es not being fi ⁇ cd are protected from exposure by covering them dating the fusing of tie oute ⁇ nost suiface.
  • the costing on tho outer surface can be made fiom a biocompatible polymer, 2$ wMch can include be both biodeg ⁇ dable aid no ⁇ ' bxodegrad ⁇ le polymers.
  • Suitable biocompatible polymers include those biocompatible polymers disclosed i ⁇ the previous section. Ii is, of course, to be -understood thai that listing of materials is illustrative but not -limiting.
  • Bi cue embodiment surface pores are closed by applying an absorbable polymer melt coating onto a shaped elastomer ⁇ c matrix.
  • the elastomeric matrix 30 acd the coating form the device, ia another mibodi ⁇ ient soifece pores are closed by applying an absorbable jpolymer solution coaling onto a ahs ⁇ od clastomoric matrix to form a device.
  • the coating and the elastomeric matrix, taken together, occupy n larger volume than the tmc ⁇ &t ⁇ d elastomedc matrix alone.
  • the coating os elt ⁇ tomc ⁇ c matrix m can be applied, by, e.g., dipping or spraying
  • the polymer content in the coating solution is fiom about 1% to about 40% by weight &x another ettibocliiB.on.t, the polymer content in the coating solution is ffom about I % to about 20% by weight Xa another embodiment, the polymer content in the coating solution is fiom about 1% to about 10% by weight, Ia another embodiment, the layers) and/or portions of the outermost surface not being solution-coated arc protected fiom exposure by covering them during the solution-coating of the outermost surface.
  • the solvent or solvent blend for the coating solution is chosen, eg., based on the considerations discussed in the previous section (i.e., in the "Imparting Bndopoia Features" section).
  • the coating on clastom ⁇ rio matrix iM may be applied by melting a fikn-formitig coating polymer and applying the melted polymer onto the dUtstometic matrix ioofay dip coating, for example, as described in Example 9.
  • the coating on clastomme matrix IOO maybe applied by melting the film- forming coating polymer and applying the melted polymer through a die, in a piocesa such as eodn ⁇ ion or coattcusion, ag a thin layer of met ⁇ ed polymer onto a mandrel formed by ⁇ lastom ⁇ ric matrix M*-
  • Die melted polymer coats fixe outermost surface aadbridges or plugs pores of Jfrat surface but does not penetrate into the interior to any significant depth. Without bong bound by any particular theory, this is thought to be due to &e nigh viscosity of the melted polymer.
  • the xcticiriated aatura of portions of the elastomcdc matrix removed from the outermost surface, and portions of the outermost elastomeric matrix surface not in contact -with the melted polymer* is maintamed.
  • the me ⁇ t ⁇ polymer foims akyef of soMcoa ⁇ oa ⁇ e eJas ⁇ cmiericmfit- ⁇ Xn
  • the processing temperature of the melted thenn ⁇ pl ⁇ stlc coating polymer is . at least about 60 0 C.
  • the processing temperature of the melted thermoplastic coating polymer is at least above, about 90 0 C In another embodiment, the processing temperature of the melted thermoplastic coating polymer is at least above about 120 4 C. ⁇ n another embodiment, the layers) and/or portions of the outermost surfiice not being melt-coated are protected fiom exposure by covering them during the melt-coating of the outermost surface.
  • Another embodiment of the invention employs a collagerKoated composite elastomeric implantable device,, as described above, configured as a sleeve extending around the implantable device.
  • the collagen matrix sleeve can be implanted at a
  • the collagen matrix sleeve can be ⁇ scfiil to help retain, the ⁇ lastomeric matrix ioo, facilitate the fotmation of £ tissue seal and help prevent leaks.
  • the presence of the collagen in clastomcric matrix iooctm enhance cellular ingrowth aad proliferation, and improve mechamcal stability, in one crabodimwt, by ⁇ 5nhan ⁇ _mg the at ⁇ fibroblasts to the collagen.
  • the presence of collagen can stimulate earlier and/or more ex>mpteteimlltratfonoftheiater ⁇ wo.
  • the previously described compOBmts, polymers and/or blends are admixed with the pharmaceuticaJIy-active ageot prior to forming the foam or the pharmaccutically-actlve agent is loaded into the foam a ⁇ w it is formed.
  • the coating polymer audpharmaccatically-activ* agent have a common solvent This can proi ⁇ de a coating that is a solution, m another ⁇ mb ⁇ dime ⁇ t, die pha ⁇ naceutically-active agent can be present as a solid dispexsiou in a solution of the coating polymer in a solvent
  • melt-coating is employed, then, is another embodiment, the ph- ⁇ n ⁇ ceutie&lly-ac-ive agent withstands m ⁇ Uproi ⁇ ssmgteit ⁇ erahires without robst ⁇ tiiddmm ⁇
  • Fo ⁇ nulatioBS comprisiog a pharmaceutically- ' activ ⁇ agent can be prepared by admixing, ftfvalc-itly bonding and/or aifeoxbing one or more pha ⁇ aceuticaUy-activ ⁇ ageuta with th «> coating of the reticulated elastomeric matrix nworby incorporating the
  • the matrix can include one or mote conventional additives, such, as diluents, carriers, Recipients, stabilizers and the like.
  • a top coating can fee applied to delay release of the pBa ⁇ t ⁇ euticaUy-active agent
  • a top coating can bo used as the matrix lot the delivery of a second pha ⁇ naceutically-activij agent
  • a layered coating, comprising respective layers of fast- and dow-hydrolyzing polymer, can be used to stage release of the pharmace ⁇ ticatly-activc agent or to control release of different pharmaccutioBlly-active agents placed in the diSerent layers.
  • Polymer blends may also tensed to-co ⁇ teolthe release rate of dificrentpha ⁇ naccutioaHy-activc agents or to provide a desirable balance of coating characteristics (e,g.
  • t elasticity, toughness t elasticity, toughness
  • drag delivery characteristics eg., release profile.
  • Polymers with differing solvent solubilities can be used to build-up different polymer layers thai may be used to deliver different pna ⁇ naceutwally-actrye agents or to control the release profile of a pbannaceuticaJly- active agents.
  • the amount of phannaceuUcaJly-active agent present depends upon the particular ptaimaceutically-active agent employed, and medical condition being treated, ID. one embodi ⁇ oen ⁇ thcpliarmaccttticaUy-ac ⁇ vc as ⁇ Qtispresr ⁇ tin Bt another embodiment, the amount of pha ⁇ nac ⁇ uficaHy-active agent represents from tibaut 0.0i% to about 60% of the coating " by we ⁇ gbt 3a another embodiinent, lije amount of pbarmaceuticaliy-active agent represents firom about O.01% to about 40% of the coating by weight Sa another ranbodiment, ⁇ ie amount of pfaa ⁇ aaceutica ⁇ y-active agent represents from about 0.1% to about 20% of the coating by weight.
  • plumnaoeutically-activc agents thatmay be administered via pna ⁇ naceutical compositions of this invention include, -without limitation, any therapeutic orpliarmaceaJic-my-active agent (including but not Umited to n ⁇ cleic acids, proteins, lipids, and carbohydrates) that possesses desirable physiologic characteristics for application to the implant site or administration via a pharmaceutical conxpositjong of the invention.
  • Therapeutics include, w ⁇ J ⁇ otrt limitation, a ⁇ tiinfectives such as antibiotics and antiviral agents; cheraothen ⁇ eutic ageats (e.g., anticancer agents); a ⁇ u ' -rejection. agents; analgesics and analgesic combinafiona-, finti-inflanrenatory agents;
  • -71- hormones such as steroids; growth, factors (including but not limited to cytokines, chemofc ⁇ ies, and i ⁇ terleuH ⁇ s) and other naturally derived or genetically engiiieercd proteins, polysaccharides, glycoproteins and Hpoprote ⁇ is, These growth fectora are described in Tho Cellular and Molecular Basis of Bone Formation and Repair by Vidri Rosea and IL Scott Thi ⁇ s, published by R, G. tandes Company, hereby incQiporatwJ ° herein by reference.
  • Additional therapeutics include thrombin inhibitors, antithtotaboge ⁇ ic ageata, thrombolytic agents, fibrinolytic agents* vasospasm iahibitors, calcium channel bbckers, vasodilator, antihypertensive agents, antimicrobial agents, antft ⁇ o ⁇ c ⁇ , inhibitors of surf ⁇ co glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, aciux inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives, anticancer chemothetap ⁇ utic ⁇ agents, anti-inflammatory steroids, non-steroidal anti-inflammatory agents, immimosuppressh'-c agents, growth hormone antagonists, growth factors, dopamine agonists, ladjotherap ⁇ utic agents, peptides, protons, enzymes, extracellular matrix components, a ⁇ giot ⁇ nsin-convexti ⁇ g enzyme (ACE) inhibitors
  • various protein.! (including short chain peptides), growth agents, chemotatic agents, growth factor receptors or ceramic particles can tie added to the foams during processing, adsorbed onto the s ⁇ rface or Vack-fflled into the foams after the foams are made.
  • the pores of the foam may be partially or completely filled -with, biocompatible resorbable synthetic polymers or biopolym ⁇ rs (such as collagen or elasti ⁇ ), biocompatible ceramic materials (such as hydroxyapat ⁇ to), and combinations thereof and may optionally contain, materials that promote tissue growth through the device.
  • tissue-growth materia include ⁇ allograft or xenograft bone, bone marrow and moiphogcnic proteins.
  • Biopolymcrs can ⁇ so be used as conductive or chemotactic materials, or as delivery vehicles, for growth fictors. Examples include reco ⁇ ibinsnt collagen, am ⁇ tql-dedved collagen, elastiti and hyaluronic acid. Bhan.iaceoiically-Bc.rv9 coatings or surface treatments could, also be present on the imrfece of the inaterials. For exan ⁇ ple ⁇ bioactive peptide seqpieates
  • RQD's could bo attached to the surface to facilitate protein adsorption and subsequent cell tissue attachment.
  • Bioactivc molecules include, mthout limitation, protein?, colkgens (including types IV and XVHJ), fibrillar collagens (including types X, D, IQ, V, Xl), FAClT
  • HBOAM hyalnonaij, hyalwenan binding proteins, mucins, ostcopontm, plasmi-iogcn, plasminogen activator inhibitors, restricto, ⁇ rglyci ⁇ , t ⁇ nascin, thrombospondi ⁇ , tissue-type plasminogen activator, urokinase type plasminogen activator, vensica ⁇ , von Willebraud factor, dextraa, arabinogalactan, d-itosaii, polyactide-glycolidc, alpnates, pi ⁇ lltilan, g ⁇ U ⁇ nwMialbw ⁇ in,
  • Additional Moactivc molecules include, withoutHmitation, cell adhesion molecules and. matrieclMar proteins, Including tbose of the immunoglobulia (Ig; including monoclonal and polyclonal antibodies), cadbsrin, i ⁇ t ⁇ grin, select, and H- CAM siiperfemffies. Exa ⁇ les include, without BmitalioiJ, AMOG, CD2, CD4, CDi, C- CAM (CELl ⁇ CAM 10$), cell swlaco galactosyltra ⁇ sffirase.
  • conncxins conncxins,, degmocollias, desmoglein, fasciclin?, FIl, ⁇ SP Ifch-DC complex, isteicellutar adhesion molecules, leukocyte common antigen protein tyrosine phosphate (LCA, CD45), LFA- 1 , LFA-3, mam-ose binding proteins (MBP), MTTClS 1 myelin associated glycoprotein ⁇ tAG ⁇ neural cell adhesion molecule (NCAM), neurofescin, xMsroog ⁇ s ⁇ , ueurotacft ⁇ , netris, PBCAM-I, PH-2( ⁇ ⁇ e ⁇ i ⁇ p ⁇ io-ifl, TAG-I, VCAM-X 1 SPARC/osteoa ⁇ ctiQ, CCNl (CYB ⁇ l), CCN2 (CTGF; Connective TJssne Growth Factor), CCN3 (NOV), CCN4 (WISP-I),
  • GH growth hoimcmeideasmgfector
  • G-CSF granulocyte colony- s&milatmg factor
  • GM- CSF graniuoejte-macropjMigo colony-stjmulatiag factor
  • insulin i ⁇ suKn-like growth fectors
  • IGF-I IGF-H
  • IGFBP iosulin-lfl-e growth factor binding proteins
  • M-CSB macropnage coIony- ⁇ dim ⁇ tbg factor
  • M-CSB macropnage coIony- ⁇ dim ⁇ tbg factor
  • M-CSB macropnage coIony- ⁇ dim ⁇ tbg factor
  • M-CSB macropnage coIony- ⁇ dim ⁇ tbg factor
  • M-CSB macropnage coIony- ⁇ dim ⁇ tbg factor
  • M-CSB macropnage coIony- ⁇ dim ⁇ tbg factor
  • Sliort-chm peptides inclnde without limit ⁇ tioii (designated by single letter amino scid code), IUxD, ⁇ IDV, RGDS, ROBS, KFDS, GSDGS, GS.GS, GRJGPXP end QPPRABI,
  • Blastomoric matrix 100 can undergo a flatter processing step or steps, in addition to reticulation and imparting endpore features, already discussed above.
  • elastomeric matrix ioomay be endoporously bydropHlizcd, as described above, by post tr ⁇ atme ⁇ ts or by placing the elastomeric matrix in. a hydxopMlic cavii ⁇ nm ⁇ nt, to tender its t ⁇ iciosiiuctuM surfaces clie ⁇ rically more leactive.
  • biologjc-Jly useful compounds, or controlled release foix ⁇ i ⁇ at ⁇ ons containing them may be attached to the endoporcms surfaces for local delivery and release, embodiments Which ace described in the copending applications.
  • annealing is carried out at temperatures ia excess of about 50 4 C. In, another embodiment, annealing is carded out at temperatures in excess of about 100 g C.
  • annealing is earned out at temperatures in excess of about 125 0 C.
  • annealing is carried - out for at least about 2 bows. ln mjother ⁇ j ⁇ diraent, amcalingis cai ⁇ iedoutforftom about 4 to about 8 hours.
  • curing at elevated temperat ⁇ res can also promote structural stabilization and long term shdf-life stability.
  • Elastomeric matrix ioomay be molded into any of a. wide variety of shapes and 2 ⁇ during its fbrmation or prodactiorL Th ⁇ ahapemaybe aworldrigc ⁇ mSgura-ion, such as any of the shapes and configurations described in the copending applications, or the shape may be for btilk stock. Stoc ⁇ itcmsirmy subsequently be cut, trimmed, punched or otherwise soaped for end use. Tbe sizing and flhajting ca ⁇ be earned out by using & blade, punch, drill Oi laser, for example. Ih each of these embodiments, the processing temperature or temperatures of the cutting tools for shaping and sizing can be greater than about 100 6 C.
  • the processing tem ⁇ eratnre(s) of the cutting tools for shaping and sizing can be greater than about 13O 10 C
  • Finishing steps can include, in one embodiment, trimt ⁇ ing of macrostaictural surface proimsiotis, such, as struts or the like, which can irritate biological tissues.
  • finishing 5tc ⁇ a can include heat annealing.
  • AimeaHog can b « carried out before or after final cutting and shaping.
  • -74- Shaping and suing can include custom shaping and sizing to match ⁇ implantable device to a specific treatment site in a specific patient, as determined by imaging or other techniques known to those in. the art.
  • Ia particttkr one or a small number, e.g. loss than about 15 in one ⁇ ntod ⁇ ne ⁇ t and leas than about $ in another embodiment, of ela ⁇ tomeric matrices lOOca ⁇ comprise an implantable device system for treating aaundedied cavity, for example, a vas ⁇ at ⁇ malfo ⁇ nati ⁇ iL
  • sh- ⁇ d and sized devices made from olastome ⁇ c matrix ioo can vary d ⁇ iaiding on tliepaiiioi j larvfiscul-u-malfoiination treated.
  • t ⁇ e major dimension of a device prior to being compressed and delivered is Scorn about 1 mm to about 100 mm. 3a. anothKcmbodin- ⁇ l; the major dimension of a device prior to being compressed and delivered is fiom about I mm. to about 7 mm.
  • the major dimension of a device prior to being compressed and delivered is from about 7 mm to about 10 mm.
  • the major dimension of a device prior to being compressed and delivered is from about 10 mm to about 30 mm.
  • the major dimension of a device prior to being compressed and delivered is from, about 30 mm to about 100 mm.
  • Elastomaric matrix * ⁇ w can exhibit compression set upon being compressed and transported through a delivery-device, e.g,. a catheter, syringe °r endoscope.
  • compression set and its standard deviation are taken into consideration when designing the pre-compiession dimensions of me device,
  • apatient is treated using an implantable device or a device system that does not, in and of itself; entirely fill ⁇ x> target cavity or other site in which the device system resides, m reference to the volume defined within the entrance to the site, m one embodiment, the implantable device or device system does not entirely £1 the target esvity or other site in which me implant system resides even after the elastameric matrix pores are occupied by biological fluids or tissue.
  • the folly expanded in situ volume of the implantable device or device system i$ at least 1% less man the volume of the site.
  • the fully expanded in situ volume of the implantable device or device system is at least 15% less than the volume of the site, In another cmbc ⁇ Minent, the fiillye3 ⁇ anded /n,rtovolun.e of the implantable device or device system i$ at least 30% less than the volume of toe site.
  • the implantable device or device system may comprise one or more ⁇ lastomeric matrices mo that occupy a central location in the cavity.
  • the implantable device or device system may comprise ono or more elastomeric matrices loo ⁇ at are located at an entrance
  • the implantable device or device system include one or more flexible, possibly sheet-like, elastomeric inafciccs too.
  • fc another ⁇ -BbodH ⁇ ent, such dastomeric matrices, aided by suitable hydrodynamics a* ttt ⁇ site of implantation, migrate to lie adjacent to the cavity wall.
  • the ftUy.cxpanded in situ volume of the implantable device or device system is ft ⁇ m about 1% to about 40% larger than the volume of the cavity.
  • cmbodi ⁇ ie ⁇ t In another cmbodi ⁇ ie ⁇ t.
  • the fullyHSxpanded in rtht volume of the implantable device of device system is £om about 5% to about 25% linger than the volume of the cavity.
  • the ratio of implantable device volume to the volume occupied by the vascular ⁇ j talfoxmation is ftom abont 70% to about 90%.
  • the ratio of implantable device volume to the volume occupied by the vascular malfoinmtion is fiom about 90% to about 100%.
  • the ratio of implantable device volume to the volume occupied by the vascular maWbnnation is fiom about 90% to less than about 100%.
  • the ratio of implantable device volume to the volume occupied by the vascular ma ⁇ fo ⁇ nation is ftom about 100% to about 140%.
  • gamma irradiation autoclavmg, ethylene oxide sterilization,, inftared irradiation and electron beam Ktadiation.
  • the use of gamma irradiation can potentially provide additional crosslinldng to enhance the performance of the device.
  • the sterilized products may be packaged in sterile packages of paper, polymer o ⁇ omers ⁇ table ⁇ iat ⁇ rial.
  • elastomeric matrix lflfl is compressed within a retaining member to facilitate its loading into a deu ' very-device, such as a camet ⁇ r or endoscope, in a compreased configuration
  • elastomeric jaa&tt ioo comprises an elastomer with a compression set enabling it to expand to a substantial proportion of its pre * compressed volume, e.g., at 25*C, to at least 50% of its pw-compressed volume, Ih another eii ⁇ odiment; expansion occure after elastomeric matrix ioOremains compressed ia such a package for typical comme ⁇ iial storage and distribution times, which will commonly exceed 3 monflis and may be up to I or 5 yeak from manufectv ⁇ eto use.
  • implantable device can be rendered radio-opaque to facilitate in vivo imaging, for example, by adhering to, covalentty bonding to and/or incorporating into the elastomeric matrix itself particles of a radio-opaque material.
  • Radio-Opaque 5 materials include titm ⁇ ura, tantalum, tungsten, barium sulfate or other suitable iaaterial known to those skilled in the art.
  • Reticulated elastomeric matrix 100 can be used as described in the cop ⁇ ndrag applications.
  • Inoneium-li ⁇ ting example one or more reticulated elast ⁇ mcric matrix IP? is selected for a given site.
  • Each, in turn, is compressed and loaded into a ct ⁇ vety-dev ⁇ ce, such as a catheter, endoscope, syringe or the like.
  • the delivery-device is snaked through, the vasculature or other vessel . system of the intended patient host and the reticulated elastomeric matrix lo ⁇ f ⁇ released l ⁇ iato the target site.
  • OIKXJ released at the eit ⁇ reticulated elastoineric matrix ⁇ OO expands iesiHently to about its original, relaxed size and shape subject, of course, to its compression set limitation and any desired flexing, draping or other conformation to the site anatomy that the implantable device way adopt
  • 20 tydrodynatnics such as pulsatile blood pressure may, with suitably shaped reticulated elastomeric matrices 100, e.g., cause the elastomeric matrix to migrate to the periphery of the site, e.g., close to the wall.
  • the reticulated elastomeric matrix i ⁇ o is placed i ⁇ or earned to a conduit; e.g., a lumen or vessel through which tody fluid passes, it will provide an immediate resistance to Qu flow of body fluid such as blood.
  • cellular entities such as fibroblasts and tissues can invade and 30 grow into reticulated dsstome ⁇ c matrix io ⁇ . B. due course, such ingrowth am extend into -the interior pores 20Oand interstices of the inserted reticulated elastomeric matrix 100. Eventually, elastomeric matrix i"° can become substantially filled with proliferating cellular ingrowth that provides a mass that can occupy the site or the void spaces in it.
  • EXHIBI ⁇ ie types of tissue ingrowth possible include, but ate not limited to, fibrous tissues and endothelial tissues.
  • the implantable device or device system causes cellular ingrowth and proliferation throughout ib,e .site, throughout the site boundary,, or through
  • tissue ingrowth is scar tissue which can be long-
  • 3i_ another embodiment ov ⁇ the course ⁇ of time, for example for 2 weeks to 3 months to 1 year, implanted reticulated et ⁇ st ⁇ merie matrix l ⁇ obecomes completely Med and/or encapsulated by tissue, fibrous tissue, scar " tissue Or the like.
  • arteriovenous malfo ⁇ naHcHW arteriovenous malfo ⁇ naHcHW
  • AVM arteriovenous malfo ⁇ naHcHW
  • arteriovenous fistulas e.g., anomalies of large arteriovenous connections
  • abdominal aortic aneurysm ⁇ ndograft endoleaks e.g., inferior mesenteric arteries and lumbar arteries associated with the 20 development of Type II codol ⁇ aks in ⁇ ndograft patients
  • gastrointestinal hemorrhage e.g., inferior mesenteric arteries and lumbar arteries associated with the 20 development of Type II codol ⁇ aks in ⁇ ndograft patients
  • pseudoaneuryst ⁇ s varicocele occlusion and female tubular occlusion.
  • a reticulated dastomeric matrix 100 is placed between fee site wall and a graft element tot is inserted to treat the aneurysm.
  • a graft element tot is inserted to treat the aneurysm.
  • a graft element is vised alone to treat m aneurysm, it 25 becomes partially surrounded by ingrown tr ⁇ ue, which may provide a site -where an aneurysm can re-form or a secondary aneurysm can form.
  • the implantable device may be immobilized by fibrous encapsulation and
  • the site may eyen faECom ⁇ scaled, mtm or less permanently.
  • the implantation site and the swnouading conduits can be imaged by arterial angiognaem Ia another einbod ⁇ wrt, they caa also be imaged to map or model the tliree-dim ⁇ ngional topography of ⁇ e intended site to faciKtate the choice of , reticulated elastomeiio matrix KHK
  • the size sad shape of the implantable device can then be estimated before it is delivered to the targeted site.
  • reticulated elastomeric matrix "W can be c ⁇ stom-J ⁇ bricat ⁇ d to fit or to be accommodated in the intended site using suitable imagine technology, e.g., magnetic resonance imaging (MRT), computerized tomography scanning (CT Scam), x-ray imaging employing contrast material or ultrasound, Other suitable magingm ⁇ thods will be known to thoacg ⁇ aEed in the ait
  • the implantable devices disclosed herein can be used as a drag delivery vehicle
  • the biodurable solid phase 12° caa be mixed, cova-ffltatly bonded to and/or adsorbed in a therapeutic agent.
  • Any of a variety of therapeutic agents can be delivered by the implantable device, fin: example, those therapeutic agents previously disclosed herein.
  • Thsg ⁇ examples are p ⁇ ovided solely for ⁇ lustrativc purposes and in no way limit the scope of the prescfit invention.
  • EXHIBIT 1 A pressure of about 3-5 psi (about 2,100-3,500 kg/m 2 ) was applied to wax particles 8(W by employing a weight W supported on. a load-spreading piste *w resting on the wax particles so as to apply compressive foio ⁇ on ⁇ ao particles.
  • the boaker was warmed to a temperature of from about 5O 0 C to about 55°C, The wax particles were closely packed in the beaker, contacting each other at about 5 to 8 contact points 8 ⁇ so particle.
  • a 10% by weight of grade S0ABIONATE® polycarbonate polyure ⁇ an ⁇ solution in. THF was prepared by tumbling and agitating the BIGNATE® p ⁇ U ⁇ ts in the THF vsiag aiotary spicier t ⁇ rning at S rpm over a 3 day period. The solution was made in a sealed container to minimize solvent loss. About 60 mL of ft ⁇ 10% polymer solution was pouted onto the top layer of the wax particles. A reduced pressure of about 5 iaches of mercury was applied to tfcs buchncr flask.
  • tht beaker was inverted end any excess particles removed ftom the plug.
  • the pl ⁇ g was placed into a stainless steel basket man air cBire ⁇ t for about 1(5 hours to remove the residual TBF, thereby providing a solid block with the interstices between the polycarbonate poly ⁇ rctaane containing the waxy particles.
  • the plug was distorted to loosen any wax particles not imbedded in th* polymer, placed into a stainless steel basket, and the basket was placed into an oven maintained at about S5°C to 9O 0 C for about 1 hour to melt out the WHX. Ifrequired, thepi ⁇ ginaybe coinprcssed to help displace excess liquid wax.
  • the porous polymer block was washed repeatedly i ⁇ hexa&e to remove residual wax and allowed to air dry.
  • the average pore diameter of the ⁇ lautom ⁇ ric matrix was fiom about 200 ⁇ x to about
  • Cylinders measuring 10, 15 and 20 ram in diameter and 5, S and 10 mm in length and cubes with IQ mm sides were cot from the reticulated material block to form prototype devices
  • Example 1 is thrice repeated, each time employing smaller particles, i,e,, having average sizes of LS, 1 and 0.5 mm, respectively. Results comparable to Example 1 are obtained in each case.
  • a solution of BIONATE* 8QA in ISF was made according to Example 1 except that its coaconteation was 1% by weight of the polyeatbonato polyurethane polymer.
  • VYBAR 260 hydrocarbon polymerpsrticleg were used except tbaitjhe particles were screened to a fotetlvely narrow diameter distribution, about l mm to about 2 mm in diameter, before use.
  • Apressrore of about 3-5 psi (about 2,100-3,500 kg/ja 2 ) was then applied to (he plate. Ai ⁇ l ⁇ catiott of the reduced pr ⁇ was heard hissing through the particles, the compression was removed, .cod the rts ⁇ lti ⁇ g "plug" was then allowed to set for about 1 hour. After this period, the beaker was inverted, and any excess particles removed from the plug. Thereafter, the THF and wax were removed as described ia Example 1 and the porous polymer block was washed
  • the polymer block as evident fcomfbe representative SEM image of that block in Figure J2,appeared t ⁇ have awtieulaied structure without any or, at mos ⁇ only a. few residual cell walls.
  • the SHM imago in Figure ⁇ displays many of the same features, e.g., reticulated solid phase ⁇ .continuous interconnected void phase -4 ⁇ .a multiplicity of struts HM that extend between and interconnect a ntiinber of intersections ISO. and a multitude of pqres ⁇ w, that are depicted schematically in Figaro 7.
  • Th ⁇ ieti ⁇ ulated nature of the polymer blo ⁇ & provides extremely favorable potential for cellular ingrowth and proliferation.
  • the density of the reticulated elastomeric matrix material was determined, by accsuxatdywdgbi ⁇ galmownyol ⁇ meofiiiatedal ⁇ l-eie 13.75 cc, and dividing the weight by the volume to obtain s density of 0.045 gm/cc or 2.8 lbs/ft 3 .
  • TT ⁇ e void volume was det ⁇ ncoined to be about 96%.
  • Cylindors measuiing 10, 15 and 20 mm in diameter and 5, S and 20 mm in length acid cubes with 10 mm sides were cut ftom tho reticulated material block to form prototype devices.
  • Pctrolit ⁇ were melted and extruded at a temperature of ftora 9O 0 C to 105 0 C tinwigh.
  • the height of Hw surface of the mixture was adjusted such that the top ofHiemisture was 22 inches (560 mm) below the bottom of the nozzle.
  • the solidified beads were collected by passing the bead/mixtare slurry through a sieve of r ⁇ cshsize ffl ⁇ all «-than #25 (710 ⁇ i).
  • the dried beads were again sieved. Twice-sieved beads in the range of from U mm to 4 mm in diameter were
  • Co-solvsats "were uaed to fb ⁇ n a polycarbonate polyttte&mie/tantaluni soMon.
  • the beads were covered with about m additional 100 mL of twice- sieved beads and gentle pressure was applied to the top of the bead layer using the base ofa cicanbeakcr, Thereafter, the solution-containing beads are placed onto a drying rack under a fume-hood for about a 3 ⁇ 4 hour period to allow the THHDMP mixture to evaporate, Then, the beads are dried under reduced pressure at about WC for a 24-48 hour perioi to remove any residual solvent. Aplugofpolymer and wax Js obtained. Th ⁇ plug can optionally bs washed i ⁇ water and kept under reduced pressure at about 4O 0 C far an additional 12 hour period to remove the water and any residual solvent, if required.
  • the plug is gcatly mechanically distorted to loosen any -wax particles not imbedded in the polymer, 'whicfo are removed. Thereafter, the plug is placed onto a ' stainless gtcel rack aad placed over a tray. The assembly is placed into an oven maintained at &om about 80 4 C to 85 0 C to for about 1-3 hours to melt the wax and allow it to flow fcom the plug into the tray. If required, the plug ia compressed to help displace' liquified wax from the plwg. The resulting elastomeric matrix is washed repeatedly in hexane, replacing the hcxane wash with fiesh hcxane at least two times.
  • the elasto-neric matrix u ⁇ dtrgoes additioflal washing lot about 2 hours in 75-SO 0 C heptane to remove any xesMual wax.
  • the elastomeric matrix is allowed to air dry at about 25 0 C
  • Tbc elastomeric matrix appears to have a reticulated structure with few o ⁇ no residual cell walls. This aspect is favorable for promoting cellular ingrowth and proliferation,
  • Example 3 is repeated employing CHRONOFLEX® C polyuretha ⁇ c elastomer in place of BIONATB ⁇ polycarbonate potyurethaae a ⁇ d using N-m*thyl-2-pyirolidone in place ofTHF. Results comparable to Ebcample 3 ate obtained.
  • the skin and subcutaneous tissue was incised, and euperfirial fascia and muscle layers were separated from subcutaneous tissue with, blunt dissection.
  • the skin was closed with p «naane&t sutures.
  • the animals were r ⁇ tnro ⁇ d to their cages and allowed to recover.
  • EXAMPLE 7 ltm ⁇ ilant ⁇ kD(mcewife Sfllective ⁇ vNcm..Pot ⁇ tts Surface 5 .
  • Apiatc ofietic ⁇ atedniat «ridn ⁇ e acc ⁇ atiingto Examplc3 isuscd.
  • a bested bladewitbaknifeH ⁇ dge is usedto cutacylm ⁇ from the piece.
  • T&e surfaces of the piece in contact with the heated blade appear to be fused and non-porous from contact with the heated blade. Those surfaces of the piece that axe intended to re ⁇ u ⁇ porous, i.e., not to0 fuse, are not exposed to the heated blade,
  • a heated blade with al-joife-edgeiB used to s ⁇ tftom the piece & cylinder 10 mm in diameter and lSmmlength.
  • EXHIBIT 1 EJCAMH-S9 Pip-Coated famlaatabk Device wfth Sclavs, v Non-Pom ⁇ ?» ⁇ ft**
  • Example 3 ⁇ piece of reticulated material made according to Example 3 is used. A coating of copolymer cootai ⁇ iag 90 ⁇ aalePA PGA aud 10 mol ⁇ % PlA is applied to the outer surface as Mows.
  • the PGA/HA copolymer is melted in an eactmder at 205 0 C and the piece is dipped into the melt to coat it Those surfaces of the piece that are to remain porous, i.e., sot to be coated by the molt, are covered to protect them and not exposed to the melt. Upon removal, the melt solidifies and forme a thin aoa-porous coating layer on the surfaces of the piece with which, it w ⁇ iss in, contact
  • Collagen obtained by extraction, from bovir ⁇ hide, is washed and chopped into fibrils.
  • a reticulated polyurethane matrix prepared according to Example 1 Is cut into a piccem ⁇ am ⁇ ing ⁇ Ommby ⁇ O ⁇ imbyimm. the piece is placed in. a sha ⁇ ow tray and the collagen slurry is poured over it so that the piece is completely immersed in the slurry, and (he tray is optionally shaken.
  • the temperature of the tray Is raised at a rate of about l°C/hourto 1O 0 C and then at a rate of about 2.5 B C/hour until a temperature of 25"C is reached-
  • the waits sublimes out of the fioz ⁇ n collagen slurry leaving a porous collagen matrix deposited wifhin the pores of the r ⁇ tici ⁇ t ⁇ dpolyur ⁇ iliaae matrix piece. T3ns pressure is returned to 1 atmosphere.
  • porous oollagea-coated polyurethane matrix piece h subjectod to further heal treatment at about 11O 0 C for about 24 hours in a current of nitrogen gas to crosslink the collagen, thereby providing additional structural integrity.
  • the sluny-coixUi-iisg mold is cooled aa i ⁇ Example 10 and placed under reduced pressure. Water is removed by sublimation as in Example 10 and, nponiemoval fiom fhe mold, a porous cylindrical plug is formed.
  • the cylindrical collagen-coated elastomer plug can, optionally, be crossEnked by heat treatment, as described in Example 10. A hole measuring 5 mm ja diameter is bored through the center of the plug to make a tube ot hollow cylinder.
  • the tube is to bo employed for tooting a vascular malformation, e.g,, an sasurysm
  • its outer diameter is selected to substantially match
  • the inner diameter of the blood-carrying vessel sod its length is selected to overlap the mouth, of the aneurysm.
  • RUB ⁇ NATE® 9433 a ⁇ dKUBINATE 9258 (each ftoav Huntsman; each comprising a mixture of 4,4''MDI and 2,4 '-MDI), were wed as the isocyanate component RlBINATE 9433 contains about 65% by weight 4,4-MDZ, about 35% by weight 2,4'-MDX and has an isocyanat ⁇ fimctionality of about 2,01.
  • RUBINATE 9258 contdns about 68% by weight 4 ⁇ '-MDI, about 32% by weight 2,4'- MDI and has an isocyanate t ⁇ nctioflality of about 2.33.
  • a modified 1,6-hexanediol carboaatc (PESX-619, Hodogaya Chemical, Japan), ie,, adiol, with a molecular weight of about 2,000 Dalto ⁇ s was used as the polyol component
  • Each of these ingredients is a liquid at 25°C.
  • "Hie crosslinCkwu ⁇ ed was gjycprol, v/Mek is t ⁇ -ftnctio ⁇ al. Water was used as the blowing agent.
  • the gelling catalyst was dxbutyltindilauratc (DABCO T-12, supplied by Air 3?roducts).
  • the blowing catalyst was the tertiary amine 33% tfietfaylenediamine in djpropylene glycol (DABCO 33LV supplied by Air Products) .
  • a s ⁇ icoae-baaed sur&ctant was used (TEGOSTAB ⁇ BF 2370, supplied by Goldsclunidt).
  • Tbs cell-opener was ORTBGO ⁇ J® 501 (snppliedby GoIdsoJaaidt). Tho ptoportioiis of
  • the one-shot approach was used to make the foam.
  • all Ingredients, except &r tke i ⁇ ocyanate component were admixed in a beaker at 25°C.
  • the ⁇ socyanatccffi ⁇ on ⁇ nt was then added w&Mgh- ⁇ e ⁇ d stirring, Tho foaming mix was then poured into a cardboard fora, allowed to use, and then post-cured fox 4 boms at 100 0 C
  • the fbsm-ing profile was as Mows: ittt3 ⁇ igtsm ⁇ ofl ⁇ 8e&., cr*ai» t ⁇ B-e o!fl5 sec., rise time of 28 sec, and tack-fra. time of 100 sec.
  • the average pore diameter of ⁇ he foam, as observed by optical microscopy, was between 300 and 400 ⁇ m.
  • Tensile testis were conducted on samples that were cot both paraJlel and perpendicular to the direction of foam rise.
  • the dog-bone shaped tensile specimens were out from blocks of foam each ⁇ xmt 125 mm thiol; about 25.4 mm ⁇ nde and about 140 nun long.
  • Tensile properties (strength and elongation at Ha ⁇ ak) were measured using ata JNSTR.ON Ut ⁇ v ⁇ real Testing It-strmn ⁇ it Model H22 with a ⁇ m-head speed of 19,6 inchea/i ⁇ mute (500 on ⁇ /mi ⁇ ).
  • the tensile strength measured in two orthogonal directions with respect to foam rise, ranged from about 40 psi (28,000 kg/ai 2 ) to about 70 p ⁇ (49,000 kgto?).
  • Tear resistance strength of the fbam was measured with specimens measuring approximately 1S2 mm x 25 mm x 12.? mm. ⁇ 40 mm cut was made on one side of each specimen.
  • the tear stxcogth was measured using an INSTRON Universal Testing ' Iotstnuncat Model 1122 with a cross-head speed of 19.6 kches/mi ⁇ ute (SOU mm/min), The tear strength was determined to be about 2.3 Jbs/inch (about 411 g/cm).
  • a block of foam is placed into a pressure chamber, the doors of the chamber -era dosed and an airtight st ⁇ is md ⁇ tained.
  • the pressure is reduced to remove substantially all of the air in too chamber.
  • ⁇ combustible ratio ofhydrogen to oxyg ⁇ gas is charged into the chamber.
  • the gas in the chamber is then ignited by a spa ⁇ k plug. The igniion explodes ths gases within the foam cell stmctars. This explosion blows out many of (he foam cell trindows, thereby creating a reticulated, elastomeric matrix structure.
  • Chemical ieticulatioa of the unreticulat ⁇ d foam of Example 12 is carried out by immersing the fbam in a 30% by weight aqueous solution sodium hydroxide for % weeks *rt25°C. th «,tl « s « ⁇ j-pte is wa&ed repeatedly oven at 100 9 C. The resulting sample is reticulated.
  • the isocyaaate component was RUBINfATB 9258, as described in Example 12.
  • the polyol component was 1,6-hexanediol cerbonatc (PCDN-980R, Hodogaya0 Chemical), with amole ⁇ dar-wei ⁇ it of about 2,000 Daltons. This polyol was a solid at 25 0 C wmle the isocyat-ate was a Hqmd at diis temperature. Water was used as the blowing agent, The geUing catalyst, blowing catalyst, surfactant and odd opener of Example 12 were used. The proportion-) of toe components -used are described in Table 3.
  • Polyol Component 100 feooya ⁇ ateCcffl-iton ⁇ -.t 53.8 Isocyaast ⁇ Index 1.00
  • the density, tensile properties, and compressive strengQi of the foam were detem ⁇ wd w described in Example 12.
  • the density of the foam was 2.5 Ibs/fr* (0.040 g/cc).
  • the compressive strength at 50% and 75% compr ⁇ ssioa was about 1? psi (al ⁇ >ut 11,900 lcgt ⁇ * 2 ) and about 34 p ⁇ i (abo ⁇ t 23,800 i ⁇ g ⁇ a 2 ), respectively.
  • the foam is reticulated by the procedure described i ⁇ Example 12. 0
  • the aromatic i ⁇ ocyaaate RIXBINATE 9258 was used as the isocyaaato corrqjor-e ⁇ t. K ⁇ BINA. ⁇ ft25S w a-iqHidat25 ⁇ > C.
  • a rcoiecolar weight of about 2,000 Daltoss was used as the polyol component and was a solid at 25"C- Distilled water was used as th « blowing agent
  • the blowing catalyst used was the
  • TEGOSTAB® BF 2370 was used as the salicon ⁇ -based surfactant ORTEGOI ⁇ ) 501 -was ttsedasth ⁇ cell- ⁇ « ⁇ r.
  • the viscosity modifier propylene carbonate ( ⁇ c ⁇ pEed by Sigma-Aldrieh) was present to induce the viscosity. This proportions of the components that were used is given in Table 4.
  • the polyol component was liquefied at 70 0 C in a KscircuMng-air oven, and 150 g thereof was wedgied out into a polyethylene cap.
  • 8.7 g of viscosity modifier was added to the polyol component to reduce -Che viscosity and the ingredients were mixed at 3100 ipm for IS seconds with the mixing shaft of a drill mixer.
  • 3.3 g of surfactant was added and the ingredients were mixed as described above for 15 seconds.
  • 0.75 g of cell opener was added and the ingred ⁇ ats were mixed as described above for 15 seconds.
  • SQ.9 g of isocyanate component was added and the ingredients were mixed for 60 ⁇ 10 seconds to form "system A.”
  • System B was pouted into System A as q ⁇ ic ⁇ dy as possible while avoiding spillage.
  • the ingredients were mixed -vigorously v ⁇ th fine drill mixer as described above 3 ⁇ r 10 seconds then poured into a 22.9 cm, x 20.3 ⁇ ax 12.7 cm (9 ia. x S in.
  • the foaming profile was as follows: 10 seconds mixing time, 18 seconds cream time, and SS seconds rise time, 2 minutes after the beg-O ⁇ ing of foaming, Le, > the time when Systems A and B were combined, the foam w ⁇ place into aredn ⁇ ilating-a-rovenra ⁇ tauied at 100 » 1O5°C for curing for 1-i ⁇ our. Thereafter, the foam was removed from the oven and cooled for 15 mirrat ⁇ s at about 25 0 C. The skin 1 WaS removed fiom each side using a band
  • the average pore diameter of the foam was from about 150 (m to about 450 ⁇ m.
  • the foUow ⁇ g foam testing was cs ⁇ ied out according to ASIM D3574. Density was mcasur ⁇ dusing ⁇ i ⁇ imcnsof ⁇ f ⁇ i-Sioiw 50l ⁇ ui ⁇ x 50n-mx25 mm. Ths ⁇ emity was calculated T>y dividing tbe weight of the sample by the volume of the specimen, A density value of 2.5 ⁇ b ⁇ /B? (0.040 g/cc) wa$ obtained. Tensile tests were conducted UnSaUIpIeSiJiSt-WeTa cat eiiher psrallel or perpendicular to the direction of foam rise.
  • the ⁇ Jog-boao shaped tensile specimens were cut from a block of foam. Each block measured about 12J ram thick, about 25.4 mm wide end about 140 mm long.
  • Tensile properties (tensile strength and elongation at break) were measured using an INSTRON Universal Testing Instrument Model 1122 wt ⁇ a cross-head ⁇ eed of 19.6 fflcfaes/ftiinute ⁇
  • the average tensile strength- determined by combining the m ⁇ as ⁇ remeixts fto ⁇ the two orthogonal directions with roapoct to foam rise, -w&s 24.64 ⁇ 2.35 p ⁇ (17,250 ⁇ 1,6505-g/m 2 ).
  • the cloagation to break was determined to be 215 ⁇ 12%.
  • Compressive testa were conducted using specimens measuring 50 sain x 50 mm x 25 mm. The tests were conducted using aa INSTRON tfeiv ⁇ ra ⁇ Testing lastfi-m ⁇ nt Model 1122 with a cross-head speed of 0.4 inches ⁇ nir ⁇ te (10 ⁇ smf ⁇ a ⁇ . The compressive strength at 50% compression -ftw detomio ⁇ d to be 12 ⁇ 3 psi (8,400 ⁇ 2,100 kg/tn 2 ). The comprese ⁇ on set after s ⁇ t>j «5ct-ng the sample to 50% compression for 22 hours at 40 0 C inon icleasi ⁇ g the compressive stress, was determined to be about 2%.
  • a 40 mm. long cut ia the long direction of each specimen was mad* through, the sp ⁇ oituentbickiiesg, beginning at the center of one 25 oini wide side.
  • the tear strcagth was measuted using ' an INSTROK Universal Testing Instrument Model 1122 ⁇ vxtl- a cross-head speed of 19.6 inches/minute (500 mm/min).
  • the tear strength was determined to be 2.9 ⁇ 0.1 lbsflnch (132 ⁇ 0.05 kg/coi).
  • Hie liquid intrusion volume of the foam was dG_e ⁇ na_edtobo4 c ⁇ ga ⁇ ifcepe ⁇ nea1 ⁇ to bo 1 TJwafy ⁇ lix (0.00142 jymt ⁇ O ⁇ / ⁇ fyce). 0 EXAMPIS 16
  • Example 15 waa Reticulation of the foam described in, Example 15 waa carried out by the following procedure.
  • the ebngaB ⁇ n to break was determined to be about 194%.
  • the post-i ⁇ ticulatioii compressive strength of the foam was determined as described m Example 15.
  • the compressive strength at 50% c ⁇ iaptessioft was dete ⁇ ained to ⁇ abo «t 6.5 psi (about 4,550 kg/ ⁇ f).
  • the pore struottire and its int ⁇ r-con ⁇ cctivity is characterized using a li ⁇ i
  • EXLAMPLB 17 yabricatioH of a Soft-Seppait-Crassimked Rgtieiilated folvurethane Maltiy
  • ⁇ polytttcrio 4,4'-MDI wittt an isocyanat ⁇ ftmctiona-ity of about 2.3 (PAFI 901. supplied by IK)W) is used as the isocyaoatc component.
  • the afkanol amine chain ⁇ xto ⁇ cter di ⁇ thanolamine (supp ⁇ d by Eastman Kodak Co.) is used.
  • the blowing and getting catalyst is a 2,2'-o ⁇ ybis(N-N ' diiiiethyi ethylmainc) /gly ⁇ lmixt ⁇ (NIAX ⁇ A4, TOj ⁇ lied1>y OSI SpeciaHie5, ⁇
  • the olofwing catalyst is the tertiary apiine 33% trie&yl ⁇ aediain ⁇ tte in djptopylcQ ⁇ glyco ⁇ ⁇ pABCO 33LV).
  • a sdlicooe-bfls ⁇ d sur&daat is used (DC 5241, et-pplied by Dow Ccwn ⁇ g).
  • the pjroportjoas of the ccm ⁇ onctits used is given m Table 5.
  • the foam is reticulated by ihe pioeedtse described in Example 13.
  • Atomogeason ⁇ solutioti ofl0% " byw ⁇ ight of BIONATB® SOA grade polycsttfeonate polyurethsne in DMSO is prepared by tumbling mi agitating UM BIOHATB pellets in the DMSO using a rotary spider turning at 5 tpm over a 3 day period. The solution is made in a sealed container to mituanize solvent loss.
  • the solution is placed in a shallow plastic tray and held at 27 0 C for 30 ⁇ ui ⁇ tes.
  • the lyophijjzertray temperature is dropped to40*C atacoolmgrateof 1.0*C/a ⁇ wte and the pressure -with ⁇ vtbe iy ⁇ pb-J&er is reduced to 50 millitoxr.
  • the tei ⁇ ssature of the ttay is raised at a rate of about OJPC ⁇ r ⁇ ur to 8 ⁇ C and held there for 24 hours, Then, the te ⁇ raturcofth ⁇ tray ia raised srt a ⁇ Et ⁇ ofabout l°C/hour until a temperature of 25°C is reached.
  • th ⁇ tray is fitrther raised at a rate of about 2.5°C/hour until a temperature of 35 0 C is reached.
  • Dtsdng lyophflizatioa, DMSO gublimeg leaving a reticulfltedpolycwbceiatepolsi-ret.miemaliix piece.
  • the pressure is rctuined to 1 atmosphere and the piece is removed from the lyophilizer.
  • Aoy remait ⁇ ng DMSO is washed ofifof the piece by K ⁇ eatecfiy rinsing it -with water, ftie washed piece is allowed to air- ⁇ i£y.
  • An implantable device comprising a reticulated resilietitly ⁇ compressible elastoxnerio matrix.
  • the elastome ⁇ o matrix comprises a polycarbonate polyurcthanc.
  • the implantable device of claim 1 comprising a reticulated dastomeric matrix comprising a plurality of pores, the pores having an average diameter or o ⁇ sr largest transverse dimetisiou of at least about 150 ⁇ m.
  • the implantable 4 «vice of clairu l t con ⁇ sing a reticulated, elastor ⁇ o matrix comprising a pl ⁇ raUty of pores, fiw pores having an average diam ⁇ ter or other largest trsimrcr ⁇ tt ⁇ mcasionof ⁇ Om ⁇ oiit 275 / ⁇ i to aboi ⁇ 900 ⁇ m.
  • the implantable device of claim 1 1 comprising a i ⁇ i ⁇ ently-co ⁇ ipressible clastocusrit matrix such that the implantable device, when compressed, from a relaxed configuration to a first, compact configuration for delivery -via a delivery-device, expands to a second, working configuration, in v ⁇ ro, at least about 80% of the sLw of the relaxed coofigflra ⁇ oniflat least oac dl ⁇ icr-sion.
  • the recovery properties of the clastom ⁇ ic matrix are such that a d ⁇ msasion of the second, working configuration is , within about 20% of a relaxed dimension of the relaxed configuration after compression to from about 50 to about 10% of the relaxed dimensioa and ⁇ wh ⁇ r ⁇ a the elastomeric matrix has a compressive strength at 50% compression, of ftom about 1 psi (about 700 fcgt ⁇ *) to about 200 psi (about 140,000 k ⁇ in 2 ), a tensile strength of ftoz ⁇ . about t psi (about 700 tg/m 2 ) to about 75 psi (about 52,500 kg'm 2 ) and an ultimate tensile dongaUoii of at least about 150%.
  • IL Theimptotabl* device of claim l. wkrti ⁇ compression sot after 22 hours compression at about 25 0 C to 25% of its thickness inouo dimcasio ⁇ of not more ⁇ xsa. -ibout 30%.
  • the implantable device of claim 1 wherein the elastomeric matrix comprises polycattemate, polya&er, potysilox ⁇ ne, pO-ywe ⁇ hfltte, hydrocatbc ⁇ i, or mixt ⁇ esth ⁇ eof.
  • the implantable device of claim 13 wh ⁇ ⁇ in the i ⁇ ticulated elastom ⁇ tic n ⁇ trix is configure to pem ⁇ wUularmg ⁇ imtrix.
  • a process for piodHciug aa dastom ⁇ rio matrix comprising a polymeric material having a reticulated structure, the process comprising:
  • wfet ⁇ intlift mold is a sacrificial mold and is r ⁇ n ⁇ yed by melting, dissolving or subliming the sacrificial mold.
  • the sacrificial mold comprises a plurality of particles interconnected one with another at multiple points on each particle, wherein0 the flowable polymeric material is contained within the interstices between the particles.
  • the particles comprise a f ⁇ st material having a melting point at least 5 0 C lower than the softening temperature of the polymeric material thai is contained -within the interstices where, optionally, the first materialS comprises a hydrocarbon wax.
  • the polymeric material comprises-a solvent-soluble thermoplastic elastomer
  • the flowable polymeric material comprises a S solution of the thermoplastic elastomer in a solvent
  • the solvent is evaporated to solidify flic thermoplastic elestomer.
  • thermoplastic elastomer is selected from the group consisting of polycarbonate pofyt-rcthancs, polyeth ⁇ r p ⁇ lyurethanes,
  • &e elastomer is a. thermoplastic elastomer selected from the group consisting of polycarbonate polyurethaaea, polye ⁇ ier polyuwfthanefl, polysiloxan ⁇ polyureiha ⁇ es, Tiydiaca ⁇ n ⁇ lyii-te-haiies, polyureftoaws with mixed soft segfnente, and mixtures thcreo£
  • Alyc ⁇ WIiaatioQprocfsssforptoducd ⁇ i.g s ⁇ elastorar ⁇ craat ⁇ Kila ⁇ ring a reticulated atroct ⁇ e the process comprising: a) fo ⁇ aing & sokt ⁇ on cou ⁇ sing a solvent-soluble biodurabl ⁇ elastomer in a solvent; b) at loast partially solidifying Ui ⁇ solution to form a solid, optionally by cooling the solution; and c) removing the aon-polyroeric material, optionally by subliming the solvent from the solid under reduced presErare, to provide an at least partially tsticulsf ed ⁇ lastom ⁇ c matrix compriang tii ⁇ elastomer.
  • K elastomer selected from the group consisting of polycarbonate poly ⁇ refliaa ⁇ s, polyotihsr polyur ⁇ anos, polysome polyu ⁇ with mixed soft segments, and mixtures thereof
  • a polymcriuatioa process for preparing a ieiiculatcd eiastom ⁇ ric matrix comprising admixing:
  • H optionally, a viscosity ⁇ r ⁇ difi ⁇ r; S to provide a crosslinked elsstoracric matrix and tcticulatiag the dastomeiio matrix by a reticn ⁇ ati ⁇ n process to provide tile reticulated elastomeriq matrix.
  • the polyol component comprises a polycarbonate polyol, hydrocarbon polyol, polysUoxanepolyol, poly(catbonate-co- hydroc-ttboa) polyol, poly(cat:boiiala-eo-silo3 ⁇ ane) polyol, ⁇ oly(hydw ⁇ arbon-co «gilo ⁇ aQ ⁇ )
  • the isocya ⁇ ate compoaeat comprises tetomethyleitt diisocyaaate, oydoh ⁇ xa ⁇ -l ⁇ iifiocyaiiate, cyelohexai-e-1,4- dii ⁇ ocya ⁇ ate, hoxw ⁇ ethyle ⁇ e d ⁇ isocyaoate, ⁇ sopk ⁇ one dii ⁇ ooya ⁇ at ⁇ , methyl ⁇ e-bis-( ⁇ - cyolohexyl isocyanate), p ⁇ hwayleoe d ⁇ socyaaate, 4,4'- ⁇ %heny3meiha ⁇ e d ⁇ socyeaat ⁇ , 2,4'- ⁇ %hmyJ(metiiaue dHsocy ⁇ ate, 2,4-tolueos d ⁇ -ocya ⁇ ato, 2,6-tolucne
  • the process otdsm.'iZ, wh ⁇ nsntiie Js ⁇ cyaoate component has an isocyanate index stv ⁇ -wheiein the isocyanate index is fiom about 0.9 to 1.029.
  • a process for preparing a reticulated composite cl ⁇ tommc implantable device comprising endopormisly coating a ietieulated ⁇ lastomeric matrix w& acoatiagmatedWsdttitedto eaca ge ce ⁇
  • the process ofclaim 46 ⁇ whramtb ⁇ coating materid comprises a foamed coating of a biodegradable material, the biodegradable materia! comprising collagen, fibi ⁇ nectin, elastin, hyaltironici acid or tabrturts thettof. 48.
  • a method of treating a vascular ⁇ ialfctmation comprising: a) compressing ⁇ & ⁇ implantable device cf claim 1 from a relaxed configurat-onto a first, compact configuration; b) delivering tho compressed implantable device to the in vivo site of the $ vascular maliomiation via a delivery-device; and c) allowing the implantable device to expand to a second, working configuration at the W ⁇ V ⁇ 'VP site,
  • TECHNiCAtHEU lite present invention relates to methods nod devices fbr the treatment of vascular aneurysms end other5 oomp3iablov8s ⁇ jularabaofmaliti(w.
  • the foi ⁇ wins 4esoriptiou of ttaofcgwwi art may in ⁇ de Insights, discoveries, und ⁇ tstandings or disol(- ⁇ ui ⁇ 3,ctf associations togtHto of dj ⁇ clo4ui ⁇ «,thfltw*c T ⁇ .0 preji ⁇ nti&v ⁇ itJoobfltvAich ⁇ ettpTO ⁇ drt ⁇ tlvfiavej. ⁇ Scn- ⁇ swhcoi-Jribalions offlieiaveBtiQn ⁇ svy be specifically pointed out below, wfaerew other such contdbuticsis of tie invention WiH 1» apparent ⁇ om their contort.
  • the csrdio-'vaacular systato when functioning properly, suppliw nutrients to all parts of flu. twdty and5 ca ⁇ ies wast* prodacteaw ⁇ y from these parts for ⁇ l ⁇ nlnation, It is ea ⁇ vtwJly a olosed-systcm comprising tliehcart, 8 pu ⁇ tt ⁇ tsi ⁇ p-ies ⁇ rt ⁇ aw»yfi»-tt the bewt, called arteries, aad blood vessels that iwira blood tow ⁇ the lwartcsdled veins.
  • C ⁇ )ittane$ arc minute vessels where outward difiut ⁇ on of n ⁇ tricnta, moluding oxygen, and inward division of wastes ti ⁇ iludittgcaiboa4i ⁇ oxide.,takts place, Cap ⁇ l ⁇ rie ⁇ connect to tiny vci ⁇ a called v «ml« ⁇ .
  • a middle layer called the tunica media iS made Of Sm ⁇ Oth «M»Cl ⁇ 45 and elastic connective tissue 55 and provides most of the girth of the blood vess ⁇ H
  • a thin outer layer 65, called the tunica adventitia, formed of connective tissue secures tfw blood vessel to the sutrou-nHns tissue.
  • Tlic tunica nied.a3S differeat- ⁇ Wood peessn ⁇ ⁇ exerted by the heart 00 tt ⁇ > walls of the trter.ci,Toi- ⁇ el- ⁇ c «waMcav ⁇ > tissue provide ⁇ the aitay 15 suf fi c i e n t elasticity to withstand foe blood presant& ⁇ dsiiddmin ⁇ eas ⁇ s mbloqdvDlttme that gc ⁇ ur with vc ⁇ tric ⁇ lar contractions.
  • Dissecting ancurys ⁇ M are coimwa to the thoracic and i-Wo ⁇ ii ⁇ al aortas the prestu ⁇ ; of a ⁇ anetaysm agamKamtov ⁇ iding tissues, capecigHy the pulsations, c ⁇ c ⁇ Bcp3 ⁇ irayal ⁇ c»B « tissue ⁇ raa ⁇ .H ⁇ ajymptoi ⁇ stic.
  • Cewbral ancurysnuf occur notlnifcq ⁇ e ⁇ tiy in. otherwise healthy and relatively youthft)! people, periiaps ia theif early thirties, and Lave beea associated with many untimely deaths.
  • Aneurysms widenings of arteries caused by Wood piessure acting on a weakened arterial well, have occurred ever since humans wali ⁇ d the plaot Ih modem times, many methods have beea proposed to treat aneurysms, for example, Greene, Jr., et al., ia U.S. Jf ⁇ te ⁇ t No.6,165,193 propose a customized con ⁇ ressible foam implant substantially conforming in size and shape with an aneurysm which Implant is produced by imaging aad modeling the particular aneurysm or other vascular sits to be treated.
  • StUl otiier patents suggest the iobcodu ⁇ a drag or other bioactive material (Gregory, U.S, Patent No.6,372,22S).
  • Other methods J ⁇ ckde attempting to rep ⁇ aaan&urs ⁇ m by introducing via a ca ⁇ tctef 4 w ⁇ aneurysm, OwwthcimteriaJc ⁇ resorpoJyin ⁇ rizes ⁇ intoa&amplugjthevr ⁇ j ⁇ ⁇ placiflg a lumen through the plug ⁇ Hastings, U.S. Patent No.5,725,56$).
  • AnotiO T gt ⁇ p of patetf ⁇ relates nr ⁇ re sp ⁇ ificalfy to sr ⁇ ⁇ lwic»,m ⁇ as string, wire or cofle4ia!-terial (Boc ⁇
  • Tbo introduced device can cany fcydrogel, drags or other Wcacth' ⁇ i ⁇ 3t ⁇ ri ⁇ tQ'3t ⁇ >iUi»ori «i- ⁇ »x»the aneurysm (Greene Jr.* et aL, UJ5. Patent No.6,299,619).
  • IFtb ⁇ aplaai does not My occlude the aneurysm and effectively seal against the -j ⁇ ewysm wall, pulsating blood may seep around the implant and the distended blood vessel well causing the aneurysm to refiam around the implant
  • Tjhe delivery mechanics of many of t& ⁇ known aneurysm treatment methods can be difficult, challenging and time consuming.
  • Too present invention solves a problem. It solves tits problem of providing art aneurysm treatment device and ⁇ tb ⁇ d wti ⁇ & is ii-eaq ⁇
  • the i ⁇ vestio ⁇ provides an aneurysm treatment device ferto ⁇ treatment of aneurysms in mammals* ⁇ ecfe!Jyin-ttai-s l wM ⁇ ttea& ⁇ coJIlarr ⁇ ble implant collapsible from ⁇ first; e ⁇ ardedconfigU- ⁇ OTwIici ⁇ the ⁇ i ⁇ lant «m support the vvall ofan aaeii ⁇ smto afiecoridTOlIapsedwtifiguraJ ⁇ aiiemysn ⁇ for cxan ⁇ le by being loacf- ⁇ l ⁇ into scaibeter and p. ⁇
  • useful aneurysm tr ⁇ aUnant devices can have sufBdftnt resilience, or otihcr m ⁇ pbanical proper ⁇ ', including Ewellabifity, to rttam to an espanded coafifiura ⁇ oa wjt ⁇ i the lumen of the aneurysm aad to support the aneurysm.
  • sufBdftnt resilience or otihcr m ⁇ pbanical proper ⁇ ', including Ewellabifity, to rttam to an espanded coafifiura ⁇ oa wjt ⁇ i the lumen of the aneurysm aad to support the aneurysm.
  • !fteferaWy ( ii£airplantuconfigui ⁇ sothath ⁇ fli ⁇ aneurysm tend to urge the implant against the aneurysm wall *
  • ft i a feature of tiwpresmtinventim that the i ⁇ wm ⁇ let ⁇ lyfi ⁇ earwuryst ⁇ orofliervascuta to do, but leather, should leave ⁇ ufl ⁇ cwat space ⁇ tfaint-w anfioiyffliibr passage of blocd to aMpteferably around lhe implant it is desJf ⁇ le that the implant be designed so that ft ⁇ r-atBwdpuIsatioasofdwblood canorgeblood between the implant and the aneurysm ii ⁇ to encoiuage fibroblasts to « ⁇ t Md, if appropriate, to invade tint implant
  • inventive ioiplants do aot ft ⁇ v ⁇ t ⁇ exactly match the inside topography of the aneurysm, and are producible from low-cost materials, they need not be custom made but can be provided ia a mge of standard shapes and sizes fb ⁇ m which, flic surgeon or oflwr practitioner selects one or more suitable elements.
  • ft is fbrtheHMW,pr*fcrabie that the implant be treated or formed of a materia, that will encourage suefa fibroblast immigration. Itisalaodesir ⁇ tethattha impli-ntta dimensional shape, and its siw, resiliency and other physical characteristics, and be suitably chemically or biochemically constituted to foster eventual formation of scar tissue that wil! anchor the implant to the ane ⁇ yaoQwaH.
  • ⁇ espwa ⁇ feble portion orayro ⁇ ris ⁇ aaiim ⁇ rw ⁇ provided vi ⁇ elevations sa ⁇ depression to &&B$&b1a ( d1kmbdm ⁇ ⁇ usit ⁇ &ecwtcrsoific « ofthe aii «-iysmtrcatotcfit device.
  • the aninirysmtrea ⁇ noflt device is pr ⁇ its phj «icaistiwtoe, &om a polyineric ibam or a reticulata Wod is ⁇ abjeofbf ⁇ c ⁇ ii ⁇ x ⁇ ssed ⁇ inr ⁇ t ⁇ A-.io,t-wit ⁇ latttcaab ⁇ fo ⁇ ied of ftltydrophubic fbain having its
  • the hydrophilic material cwrics a pha ⁇ nacol ⁇ gic agest for example elastin to foster fibroblast pxpHferatioo, K is also within the scope of the invention for the pharmacologic agent to include sclerotic agents, inflammatory induction agents, growth factow capable of fostering fibroblast proliferation, orgs ⁇ ericsHycnginBCTed- ⁇ orge-ietiwUyactmgthcrapeatics.
  • tfce present invention preferably are dispensed over time by the kapte ⁇ k Jfoco-pojarion of biologically active agents in the hydrophilic phase of a composite foam suitable Has me ra the practice of tfce present invention is described fa Tban ⁇ Qn XJ.S. PG PUB 20020018884 tatne pMyik ⁇ &ei heawbelaw.
  • the inv ⁇ nticm provides a method of tcra ⁇ igan a ⁇ ei ⁇ ysm comprising the stops of: a) imagmganto ⁇ iiryr ⁇ to twteflat ⁇ dto b) sdectingatt anciiiysmtrealn-Bntd ⁇ viM acco ⁇ ling to claim 1 for tise m c) iatp-auting the an ⁇ iay ⁇ mtwatment device i ⁇ tetl- ⁇ aaeii ⁇ ysm.
  • ⁇ ecltosc ⁇ ⁇ lant ⁇ i ⁇ laat ⁇ weth- ⁇ foadedifltoaiii ⁇ ra.v ⁇ rolarca ⁇ Lfdtsircd,tfa ⁇ i ⁇ la ⁇ to can Iw pn ⁇ in a stedle pacte ⁇ ⁇ n a pi ⁇ » ⁇ cafli ⁇ t ⁇ r.
  • fl implants ca ⁇ be made jsvaflabl* in an es ⁇ ajidad state
  • Tins position may not be the final position w&ich may fee attained as a result of movement of the h ⁇ ht ⁇ by natural forces, notably blood flaw.
  • Figure 14 is a side view of an artery with layers partially cut away to ilhrttcat ⁇ the anatomy of the artery, figure 15 is a longitudinal cross section of Baart ⁇ w ⁇ * saccular aneurysm;
  • Figure 16 is a longit «dij ⁇ crojs s ⁇ onofanart ⁇ withaft ⁇ ifo ⁇ nai ⁇ Jiysn ⁇
  • Figure 17 is a Wp view of an artery at * t ⁇ &rcatwn;
  • Figure is is a top view of aart ⁇ at&t ⁇ ftiH ⁇ ont ⁇ saecu ⁇
  • Figure 19 Ls a side view of an cmbodirneat of an aneurysm tteattucnt iiaplant in accordance with the prer ⁇ it inve ⁇ tioa stapedis ⁇ tii ⁇ topofthcbowU
  • Figure 20 is a topi>-aflviewoftb ⁇ nbod ⁇ j» ⁇ tilhmr-it ⁇ dinPigur ⁇ i9;
  • Figure 21 Ls a p ⁇ a ⁇ ectivcvicwofaa e ⁇ il)Q ⁇ ii ⁇ taacet ⁇ d ⁇ lite ft wla ⁇ glass, wth a 1» ⁇ porticm, voliittm poitit ⁇ sid ⁇ ⁇ wd ⁇ s;
  • Figure 22 is a lo ⁇ gi4udi ⁇ c ⁇ isoia ⁇ c ⁇ oa ⁇ a$a ⁇ c ⁇ l ⁇ 8Qeury ⁇ with etok ⁇ iimeDts of tl ⁇ present invmto
  • Figure 23 Ls a tongitwH ⁇ -tl ClOSS SOCtlo ⁇ irfmaxtety&B ⁇ tet ⁇ 1 ⁇ BMtC&ed iaVif ⁇ 22 farther iU ⁇ !ti «t ⁇ g the aMtio ⁇ of a sheath k die lnmn of ⁇ art ⁇
  • Figure 24 Ls a lon ⁇ tadiiaScioss sectioiftofan artery MmUaTtO that flh ⁇ iHustialuigattasAo ⁇ mtofite
  • Figure 25 Ls a side vie?/ of an cmbodims ⁇ t in accordance with the present similar to Figure 19 wh ⁇ f ⁇ tfac bQttomstufiu»ofth ⁇ b ⁇ lfaro ⁇ nd ⁇ fd;
  • Figure 27 is ap «- ⁇ cctivevi ⁇ ew ⁇ fMemb ⁇ ) ⁇ &»- ⁇ tDf& ⁇ whc ⁇ em the side -walls of ⁇ bowl portion an substantially jtraight;
  • Figure 2S is a pcr ⁇ trvcviwv ⁇ f ⁇ i ⁇ odH ⁇ -tofthepresefltiw whecd ⁇ a faoitomoftto bowl portion lias an obtuMcuiWur ⁇ awl little or no side 1 WaIk; Pii;ure2! is * «idc vicwof an emb ⁇ X-J ⁇ )ratina ⁇ Mrda ⁇ cc V ⁇ fKtsO ⁇ section ⁇ cut longit ⁇ dinally;
  • Figure 30 is a bottom view of the embodiment of the Jtt ⁇ scnt iove ⁇ tio ⁇ illustrated ⁇ a Kgure 2» flirthcr illustrating a pattern of the sections;
  • Figure 31 is a side view of en alt ⁇ uiitive embodiment of the present invention similar to the erabodimcnt of Ftguiti 29 whcrm the « ⁇ ctioi ⁇ a « separated by ⁇ ja;
  • Figure 32 illustrates aa embodiment of the present i-V ⁇ otion similar to the en ⁇ od&ne fl t of Figure 31 wherein the top and bottom are minor images about a plane through the* center of the implant;
  • Hguw 33 isados j -- « j ctional vi ⁇ wofthece ⁇ tetporti ⁇ « ⁇ i!lusteitedilttKgttr ⁇ 32 and viewed along line 20-20 "whereia the sections are disposed only around the perimeter,
  • Figure 34 is a cross-sectional view of the center portion illustrated it Figure 32 and viewed along line 20-20 wherein the sections are disposed through the entire cross section of the embodiment j and JFIgS.35-37 illustrate several embodiments of porous elastomeric
  • the present ⁇ m ⁇ on relates to a -tyBtemsutfn ⁇
  • the present invention provides an mieucysm treatment d ⁇ derived to be pe ⁇ rn ⁇ raflyH»etfedii-to an aneui ⁇ ft ⁇ implants described in detail below can be made in » variety of sizes and shapes.
  • the smgeon bring able to choflswtii ⁇ best aiz ⁇ and shapo to treat the pa ⁇ at*s aneurysm.
  • the iaventivo aneurysm treatment device is designed to give physical s ⁇ to the wealed w ⁇ fihtmcmy&m, and ⁇ & t ce or eliminate the pulse pressure *jasrtcdon these walls.
  • ⁇ tataera ⁇ OT,i-» ⁇ i-vra ⁇ ivs- ⁇ »u ⁇ can cany one or « ⁇ ⁇ of a wido range of beneficial drugs and «:b ⁇ cmcaUtIi ⁇ tanbet ⁇ I ⁇ a5 ⁇ attl-ea--fectc!d site j ( or various treatment ⁇ uch as to aid in healing, foster scaring of flt ⁇ aneurysm, prevent fotiiier damage, or reduce rijk of trcatracatfeihnu.
  • these drugs aodcheBiicablocaUy. en ⁇ kjy ⁇ an methods of the iuv ⁇ ti ⁇ . their systemic aide tSects areteduced,
  • implant 105 sho ⁇ id be sufficiently large to attenuate the pulse pressure exerted on the walls of the btood vessel to reduce the risk of further damage and leaking of die aneurysm.
  • More than one implant may be used for & singleatittirysjn.
  • the volume of the implant, or implants, msltu is preferably significantly less than the volume of the aneurysm, for example no more than $0 percent of the interior volume of the aneurysm, more preferably no more than 75 percent, referring to the volume of the abnormal structure outside the normal outer periphery of the host artery at the site of the aneurysm.
  • the volume of an individual implaat is preferably no more than about 60 percent of Qw aneurysm internal volume, wort preferably fiom about 10 to about 40 percent of the aneurysm internal volume.
  • the surgeon determines that the aneurysm can handle the blood flow, the surgeon will utilize the embodiments of the implant described below tbat allow blood flow. However, if the aneurysm ⁇ leaking, or the surgeon dotcro ⁇ - ⁇ tlw walls of the aneurysm are too thin to handle the blood flow, the eurgeoa may choose an embodiment that seals off the aneurysm.
  • projection 125 way have a thicla ⁇ es ⁇ of approximately 10 to 40 percent of the diameter defined by sid e walls 205.
  • the pwjc ⁇ oa ⁇ iay be tMdw or narrower to serrcdesdredpu-pos ⁇ .
  • outer surface 215 of impiaut 10s U relatively smooth and designed to contact the majority of the inner wall of the aneurysm.
  • outer surfaces 165 ⁇ &d 215 can he eoated, after fabrication of the implant, with functional agents, such as those described herein, optionally employing an adjuvant that secures the Junctional agents to the ' ' ile.
  • Such external coating whld j may bo distinguished ilfconi internal Coat ⁇ ngs provided within and preferably flirougho ⁇ ⁇ porcs offt fotLOi i ⁇ laat ⁇ descni ⁇ dhw ⁇ i ⁇ . CM promote fibroblast giwtb.
  • implant 105 may have any desired shape in plan, although ⁇ ymrasttical stupes such as elliptical or oval are preferred. Nevertheless, p ⁇ lyg ⁇ qal shapes such u hexag ⁇ Furthermore, H will be appreciated that the cross eectional shape in plan need not be geometrically regular.
  • Base 245 can be of any ge ⁇ nietrie shape, in flje eiri ⁇ Pr ⁇ QtfagBxim ⁇ iocc ⁇ leeaf bx ⁇ WSmiim ⁇ v ⁇ bast zisteiictAumnMS.
  • Bowl 265 can be straight, or as i ⁇ the prof ⁇ wd embodiment, have & s ⁇ it concavity. Attaching to and integral tvith column 265 at an end ftirthcst from the base 245 is bowl 2S5. Bowl 2SS has a rounded bottom 325 with sidewalk
  • E*;htcgiott of irnpUnt 225 serves a ⁇ aitic «larp ⁇ -posc.
  • Bowl 285 is Itaertc4 into an aneurysm and provides support to the walls of the aneurysm column ws provides support to the neck of the aneurysm, B» S e 24S can remain outside of the ancuiysm, i ⁇ the lumen of the affected artery and serves to keep implant Z25 in pj ⁇ g, Further, if desired in some variants of implant 22*, bast 245 can be placed against tfco antrum of the aneurysm and the smounding arterial wall a ⁇ d serve to seal off the a ⁇ urysi ⁇ .
  • implants i6$ and 22S can be «aday formed of tow-cost materials and can accordingly be provided in a range or kit of difforcwt sizes aad shapes fiom which the surgeon chooses cue or mow to use for a specific treatment ftis notaocoothytoinapthefi ⁇ r ⁇ ji ⁇ m
  • Grccno et al teaching.
  • awwyun has bw ⁇ identified using suitable imagins technology, such as a magnetic resonance image Q/ ⁇ tfj, con ⁇ pufariz ⁇ d tomography scan (CT Scan), x-ray imaging wthco ⁇ tt- ⁇ jiri ⁇ iial or ⁇ ltiasoimitJw ffeels Wi ⁇ d b ⁇ suit ⁇ ancuD ⁇ sin, both in sh ⁇ and ⁇ iw, llw chosai in ⁇ lant or io ⁇ lants are then loaded Mto a ⁇ mtra ⁇ s ⁇ Jwcatteteriiiacompwas ⁇ dsiaU!.
  • suitable imagins technology such as a magnetic resonance image Q/ ⁇ tfj, con ⁇ pufariz ⁇ d tomography scan (CT Scan), x-ray imaging wthco ⁇ tt- ⁇ jiri ⁇ iial or ⁇ ltiasoimitJw ffeels Wi ⁇ d b ⁇ suit ⁇ ancuD ⁇ sin,
  • the implant can be> sold in a sterile packagein ane3 ⁇ a ⁇ dcdstate,3ndihflm3igwm ⁇ ttosit ⁇ Qfi ⁇ lan ⁇ w or chute that compresses Ha iaaplant &r low ⁇ ng into ftp cadicter,
  • implants 105 and 125 can iiOTiediatoly protecttlw aneurysm waUsffo ⁇ aiig-itothOTOTse exploit a parties w « ⁇
  • implants are preferably each substantially soatethim the aneurysm itself, suidr ⁇ can be relativoly soft, having only enough resiliency to maintain their shape in situ, the risk of the implant ruptn ⁇ fogtt otherwise further ag ⁇
  • implant 105 and implant 225 can be used in combination, wherein the projection 125 of implant io; can fit at least partially inside void s ⁇ sof implant 225.
  • implant 105 can sit above iicpiant 225 with little or n ⁇ contact between implant iosard implant ⁇ 5-
  • Tl-einylantt dsfl-rtbedin ⁇ oi-i ⁇ sectioned sheath 3S5 such as supplied by Boston S ⁇ enti& Cot ⁇ o ⁇ fimtI ⁇ i8 -r ⁇ li «4totb ⁇ waUofth ⁇ arfe ⁇ such thai the neck ⁇ s o f the a ⁇ « ⁇ blood flowto the aneurysm is cut ofL Altcm ⁇ tiv ⁇ ly.
  • sheath 385 can be perforated to allow blood flow into the aneurysm.
  • FIG. 25 implant 2105 ia s ⁇ u ⁇ lar to i ⁇ l ⁇ t i «5 iUustiated in Figure lSwith the difference that the bottom surface 21S5 is rounded such that the curvature of bottom surfece zi ⁇ s Is continuous with that of side walls 2205.
  • Bottom surface 2issand side walls 220s can form B substantia ⁇ hen ⁇ pheric st ⁇ pe.
  • Implants UKand 210s are designed such that their outer surfeco 205,2255 respectively contact the inner watts of the aneurysm 15.
  • the center projections 125,212s cot provide support and distribution of the forces exerted
  • Figure 26 las a skeletal structure with open spaces betw ⁇ ea nVlike supportive msmber ⁇ . Once inserted into the aneurysm ribs i405can support the aneurysm walls and if desired may release one oxrdore pharmacologic agents. Spaces such as uis between the ribs allow for blood to flow through tho aneurysm.
  • Tfa ⁇ embod-rocat of ! Figure 29 and 30 iUastrates a bullet Shaded insert 550S with a bottom 5525, height 5545 and tap section 565 *il integrally formed TIw tc ⁇ sectim COT be ofany-iap ⁇ swch as pobty, flattened or as inthcprcftirpd crnbodiinent, substantialfy curved.
  • the heights&ts which makes up the side walls of implant S505 is relatively ItXa-Jg ⁇ and bottom 5525 csa be pf any strictly » aUEhaswunded,poniiy,orasinihe preferred C-nbodlmentrelaiively flat Fig ⁇ »30, a bottom view of implant ssos show* the slices ⁇ SS made in implant 5505.
  • ⁇ he slices 5585 create sections 605 of Implant 5605. These sections 5605 provide increased surface ana of implant 5505 for more contact of the aneurysm and blood with the added chemical agents and allow implant 5505 to better conform to the afaape of an aneurysm as it «q>ands.
  • the sections tfSOS or implant 6S05 have space 6625 bctwee-t ⁇ mresembhns tho tentacles of an octopus or spaghetti.
  • Figure 32 illustrates an implant 7505 ⁇ vherein the top 7565 and bottom 7525 portions are substantially solid and the side WBIIS comprises thin strips 7m.
  • M is illustrated in Figures 33 and 34 which illustrates two embodiments of : implant 7505 tt ⁇ cross section of implant 7505 can he hoiiow 7625 where the side wall strips 7605 just around the perimeter of implant 7505 (Fig.30).
  • the cross se «ioas as viewed along lines 20-20 can be made up ⁇ tsixipumis ⁇ aitaJ ⁇ up sut ⁇ t-mtially the entire cross section of implant 7505.
  • Fig.35 shows a generally tubular implant 9305 formed Of suitable porous ⁇ last ⁇ ffl ⁇ rie material as described elsewhere beam having an outer form »325 , which is that of a tight cylinder which is internally sculpted out to enhance the overall compressibility or the implant 9305, , wjt ⁇ a ⁇ open-ended hollow volume 9345 which is also right cylindrical, or may have toy other desired shape.
  • Pig. 36 illustrates a bullet ⁇ iko implant 9365 having a blind hollow volume 9385.
  • Fig.37 illustrates & tapered, frustO-CQHical implant 94QS which has an open-ended fttoltow volume 9425.
  • Implants 9365 and 9405 sue generally similar to implant 9305 and all three wpismts 9305, 9365 and 9405 may have any desired external or internal cro ⁇ -a ⁇ ctio ⁇ al shapes including circular, tq ⁇ m, rectangular, polygonal and so on. Additional possible shapes are described heroi ⁇ below.
  • implants 9305, 9365 and WOS may be "solid", with any of the described exterior shapes, being c ⁇ nstnicted throughout of porous material and lacking a hollow toterioroa a macroscopic scab, Desirably, any hollow interiof ianot closed but is macroscopicaUyopea to ⁇ wi ⁇ grcs ⁇ of fluids, i.e. fluids can directly access the macroscopic interior of the implant structure, eg. hollows 9345, 9385 or 9425 «uJ cm also migrate Mo the ⁇ t ⁇ Jtot through it ⁇ po ⁇ snotwork,
  • the outer.pcripiwrics of implants 9225 can have m ⁇ ro complex, shapes for desir ⁇ pwposes, for example, cottugited. It is contcinplatedttm a tapered or bullet- ⁇ hqx ⁇ outer profile may fic ⁇ itate delivery, especially of iat ⁇ rin ⁇ lants arriving after a proportf ⁇ a of the intended group of implants has already been delivered to the tafget site at-dnayoffertsi ⁇ tanc ⁇ toiiie acTOnr ⁇ iod-doiiof newly arriving iroptoatt.
  • HK hollow volumsa can constitute any stit ⁇ leprop ⁇ ttitt oftt ⁇ re. ⁇ percent u/Jth other useful voli ⁇ nes being in the range ofabout 20 to about 50 percent
  • ⁇ nd-V-du-tt onefi of the shaped implantt can have any one of a range of configuration ⁇ , ⁇ nrfnf ⁇ ing ry ⁇ inrtri ⁇ t conical, frt-stoco-ucal, Imllet ⁇ baped, ringHShaped, C-shapcd, S-shaped spbd, helical, spherical ⁇ elljptieal, el ⁇ psoidal, polygonal, stw ⁇ ikc, compounds or c ⁇ btaati ⁇ ns of two or more of the foregoing and other such configuration as may be suitable, as will be apparent to those skilled in the art solid and hollow en ⁇ odimeats of the foregoing.
  • Preferred hollow embodiments have an opening or an open fi ⁇ e to permit ⁇ Jiwct fluid access to tfce interior of die bulk configuration of ⁇ ⁇ itnp ⁇ ant,
  • Other possible embodiments can be a$ de ⁇ CTflwd with rej ⁇ c ⁇ ce to, or as shown in/iFi ⁇ re 21, and Figures 23-34 >f the accompanying drawings).
  • StiUflarther possible embodimentt of shaped in ⁇ lant include n»dSly ⁇ ng the fot ⁇ goi ⁇ g
  • faipu ⁇ rta having solid or hollowed-out, relatively simple elongated shapes such as cylindrical, bufleHilw and tap ⁇ wd shapes are contemplated as being particularly useful in practicing Qa invention.
  • the individual implante in an occupying body of implants employed for treating a vascular problem can bo identical one 1 KdQt another or may have different shapes or different size* or both.
  • Cooperatively shaped or cooperatively sized implants may fee employed to provide good packing within Ao target volume, if desired.
  • Th* invention also includes use of a number of ittpliuito, for ew ⁇ lo in the range of flroin about 2 to about 100,or . ⁇ t-i ⁇ nngeof&&:mabott4t ⁇ &b ⁇ implants 9305, 9365 and 9405 or c ⁇ er iii ⁇ l ⁇ tsdescnTjcdtieffijai ⁇ svbem ⁇ d&rthigpurposc,
  • Oert ⁇ embodiments of the inveiition coii ⁇ compressible and exhibit resilience in their rec ⁇ vety, that have 3 diveraity of applications sod can be ei ⁇ t ⁇ y ⁇ by?t ⁇ ofexa!r ⁇ le,mina « ⁇ artorio venous ⁇ all ⁇ c ⁇ oi ⁇ artttial eniboliz-dSon OT pba ⁇ nacc «ticil-y-activ ⁇ agent, eg., for drug delivery, ⁇ hr ⁇ , ss used herein, the term "vascular raaifonaation'' includes but is not limjted to anei ⁇ ysms, arterio venou-s malfiinctioDs, arterial etnbolisat.o ⁇ « and other -vascular abnormalities.
  • biodu ⁇ sble elastoiwar products for in vivo deliveiy via cata ⁇ tw, endoscope, arthrpscopeila ⁇ mscope f Cy ⁇ QaOTpe, syringe cre ⁇ ex suitable ⁇ teUv «y- ⁇ Ievi «ai_d cMbesaa ⁇ ct ⁇ -ify extended periods of time, fbr example, at least 29 days,
  • Various implants have long been considered potentially useful &r local in situ delivery of biologically active agents and more recently have been contemplated as useful for control of e ⁇ dovascular conditions including potentially ⁇ Te4hreateni&£r conditions such as cerebral and aortic abdominal aneurysms, arterio venous ⁇ ial ⁇ incdon, arterial embolization or other vascular abnom ⁇ tics.
  • an implantable system whicb can optionally reduce blood flow ⁇ w to fh ⁇ pressure ⁇ irop caused'by additional resistance, optionally cause immediate thrombotic response leading to dot fomaUem, and eventually lead to fibrosis, Lc 1 , allow for and stimulate nsft ⁇ al cellular ingrowth and proliferation into vascular malfotmatio ⁇ s and the voidspac ⁇ of implantable devices located in vajcnlw malfonmtiona, to stabilize and possibly seal off wch features ia a biologically sott ⁇ d, eflfcc ⁇ ' ve and Jesting manner.
  • J ⁇ c «tl turbulence and stagnation points iniiuccd by the at ⁇ lwtfable device surfe ⁇ ? may lead to platelet activation, coagulatioa, ⁇ rtffi-bi ⁇ fb ⁇ nation _md dotting of blood.
  • the implantable &r ⁇ e or d ⁇ vt ⁇ system causes cdlul» tlr ⁇ u ⁇ utthesito,througt ⁇ theatebo ⁇ the site.
  • c ⁇ time.fbJs it-d ⁇ txdfanovs&ciiiarc ⁇ k ⁇ la ⁇ t- ⁇ le device to bo i ⁇ cotpor-Ucdmto the cond ⁇ T ⁇ 35 ⁇ iasiow£hcaQ leadtov «ycl ⁇ nrtivort ⁇ -sta ⁇ cc to migration of the implantable device over time.
  • Ih another ⁇ ibodim ⁇ iitvihc tissue ingiowfii is sew tissue ⁇ ioh COT be Iong4astinft innocuous and/or mccbs ⁇ iealfy stable.
  • implanted reticulated ehstome ⁇ ci ⁇ atrix. becomes completely Gllcd and/ot encapsulated by tissue, fibrous tissue > scar tissue or the UIw,
  • the features of the implantable device, its fliactionalify and i ⁇ t ⁇ tactioa wi ⁇ conduits, lumens and cavities in the body, as indicated above, can be usefiif fa treating a number of arteriovenous xnalf ⁇ rr ⁇ atkt ⁇ C 1 AVM") or other vascular ahnotmaiities.
  • AVMa anomalies of ft ⁇ dajg and draining veins
  • arteriovenous fistulas e.g., anomalies of large arteriovenous connections
  • abdominal aortic aneurysm autograft cadoleais *.£, hiferior mesenteric arteries and lumbar arteries associated with ⁇ vo development of iypc H e ⁇ doleaks in ⁇ rtd ⁇ g ⁇ if- patient.
  • AtcUcn»l»t «delastoraeric matrix is placed between a target site wall and* graft element that is inserted to t ⁇ at the t ⁇ ittysm.
  • a graft element is used at ⁇ tw to treoi ⁇ aneurysm, it becomes paitiaUysmfwrndad by ingrown tissue, which may provide a lite ⁇ ete ⁇ o ⁇ eui ⁇ mcanre-f ⁇ mioraiccondw ⁇ eui> ⁇ fflcTMfonn- In some case ⁇ , even after the graft is implanted to treat the aneurysm, undesirable occlusions, fluid emrap ⁇ wnts or fluid pools may occur, thereby ceducii ⁇ t-mefficai ⁇ ofth ⁇ in ⁇ la-st ⁇ dgn ⁇ .
  • fluid i ⁇ rapnie ⁇ ja or fluid pools can be avjri ⁇ tissue, including fibrous tissue sad/or endothelial tissue ⁇ secwn ⁇ agaiiist Blood leaiag ⁇ or risk of heano ⁇ rnage, and effectively shrunk.
  • Ih one emboo ⁇ nient,iiw ic ⁇ lantable device may be irtiaob ⁇ fiorow encapsulation end tho site may eveo become sealed * ⁇ Mr ⁇ orlesspe ⁇ aas ⁇ ntry.
  • ⁇ bod ⁇ wnt & patient is treated using an iii ⁇ -ants ⁇ ble device or B device system that does aw, itta ⁇ d of itself enfesly fiU ⁇ » target cavity or other site in ⁇ Mentha device Si ⁇ tem resides, in ndferenoo to the yml ⁇ ffna A*fineA within Htm rmintnrn t ⁇ Jhn cite.
  • the implantable device oi device system rnayco-npriseoneorinore ebstomeric matrices th»t are Iwi ⁇ ted at in entr ⁇ implantable device or device system include* one or more flexible, possibly sheet-fite, elastome ⁇ matrices. Ih another embodiment., such elastomeric matrices, aided by suitable hydrodynamics at the site of implantation, migrate to He adjacent to the canty well
  • aapmg and siang can include cut f om ⁇ apmg ⁇ treatment site to a specific patfonfc, as dttormined by imagi ⁇ j: or othor techniques known to those in the art
  • one or at least two comprise an implantable device system for treating an imdesired cavity, for example, a vascular nalfb ⁇ uation,
  • Implants useftil in this invention or a suitable hydrophobic scaffold comprise a porous reticulated polymeric matrix formed of a biodurablc polymer that is rcsilicntly-comprcssiblc so as to regain its shape after delivery to a biological site.
  • ⁇ hp structure, foorphology and properties of the dastoxnerie matrices of this invention can be engineered or tailored over a wide range of performance by varying the starting materials and/or the processing conditions for different fractional or therapeutic uses.
  • Thepomiabi ⁇ durable elastomericrmtrixis coBsi ⁇ interior ⁇ t ⁇ ictut* comprises interconnected open poiresbcmndedb ⁇ int ⁇ reecqons raw const-we too ⁇ ono structure, me continuous interconnected void phase is the principle feature of a reticulated structure.
  • PxefKted scaffold ⁇ ratti ⁇ aU ⁇ t)w iicjdants - ⁇ inquired liquid pwmeabiUty and thus selected to p ⁇ at blood, or other appropriate bodily fluid, to access interior suc&ces of the implants, wh-ch optionally x ⁇ bo dnig- ⁇ jeaiing, dining th ⁇ xra ⁇ nded period of ⁇ npls ⁇ ta-ioo. This happeiisdi- ⁇ to ⁇ presence of inte ⁇ xm ⁇ ectc ⁇ pansagew ⁇ or flmd peiineabil ⁇ ty p ⁇ diog fitt ⁇
  • any of a VOTcty of materials ⁇ M ⁇ gth»fb» ⁇ Aprofetrcd fbamor other por ⁇ us material is aco ⁇ ressible, li ⁇ twdght material, cbosen for its structuial lability in situ, its abili ⁇ r to support die drag to be delivered, for hi ⁇ liquid pamacabffiiy and for an ability to substantially recover pie-compression shape and size within the Madder t ⁇ provide, when loaded with appropriate substances, areserv ⁇ ir of biologic agents that can be released into the blood or other fluid. SuftaWe materials are fttrtber described herei ⁇ below.
  • aa implant can t» compressed ftom a relaxed, con ⁇ guratio ⁇ or a size and shape to a compressed size and shape tm4et ambwut conditions, e.g, at 25 9 C to fit f ⁇ to the introducer instrument for i ⁇ awtioj. into the bladder or other suitable internal body sites for in vivo delivery.
  • an implant may bo supplied to the medical practitioner perfott ⁇ bg the implantation operation, in a compressed configuration, for example, contained in ft package, preferably a sterile package, Tlwrwitt ⁇ Jicyoftbeeta ⁇ t ⁇ in ⁇ cr ⁇ a ⁇ implant causes H to recover to ft working size and configuration fat ajtu, at tho fanptentation site, after being released from fa compressed state within the introducer instrument
  • the w ⁇ rfcing size sad shape or configuratio ⁇ caii bo substantially similar to original size ⁇ d shape after the in situ recovery,
  • Atl ⁇ ajtpartially hydrophobic po ⁇ m ⁇ lc scafibld d-at ⁇ ials are 2 ⁇ dRs ⁇ - ⁇ i ⁇ ofhff materials in ⁇ ybe ⁇ sofiil materials are ftef ⁇ ab ⁇ y ctestora ⁇ ri ⁇ in that tl ⁇ y can be COTI ⁇ WJ ⁇ and c ⁇ resiliently recover to substantially the pw-conaprcfisiion state.
  • a paitialfy hydrophobic scaffold is pi ⁇ fctably coustructcd of a materiel selected to b$ sufficiently Wodurable, ftr tiie iat ⁇ aded period of iaiplantaiion tnat the ⁇ 1- ⁇ Iai.t ⁇ viUnotlo ⁇ ittBtrHCtii ⁇ integd ⁇ d ⁇ tridgiii ⁇ implantation time in a biological e ⁇ vircnmcnt
  • foonoeadw-itne ⁇ thcdesi- ⁇ pc ⁇ ⁇ iis measure is intended to avat ⁇ swfifold tpatcriah that may decompose or degrade info fragments for example, fragments that could have undesirable effects such as causing an unwanted tissue response.
  • the void phase, preferably continuous and interconnected, of the a porous reticulated polymeric matrix that is used to fabricate the impl&nt of this invention may comprise as little as 50% by volume of the elastomcric matrix, referring to the volume provided by die interstitial spaces of elastemeric matrix before any optional interior pore surf-ieo coating or layering is applied- Ja one embodiment, the volume of void phase as just defined, is from about 70% to about 99% of the volume of elastameric matrix Ih another ejabodiment, the volume of void phase is fiom about 80% to about 98% of the volume of eUst ⁇ msric matrix. Ih another embodiment, the volume of void phase is from about 90% to about 98% of th» volume of elastorawic matrix
  • a pore when a pore is spherical or substantially spherical, its largest transversa dimension is equivalent to the diameter of the pcae.
  • a pore When a pore is non-ajdierical, for example, ellipsoidal or tctr-thcdral t its largest transverse dimension is equivalent to the ⁇ eatestdi-rt ⁇ wwitbia fli ⁇ porefiomo ⁇ epotv ⁇ wrfkceto another, eg., the major axis length for an ellipsoidal potc or the length of the longest side for a tetrahedral pore. For those ⁇ ldMed in the ail; one cr ⁇ roirtinety diameter in tnicro ⁇ s.
  • the average diameter or other largest transverse dimension ofpores B ftora about 50 ⁇ m to about 800 ⁇ at(i ⁇ about 300 to 25 pon» per linear inch), preferably from 100 ⁇ m to 500 ⁇ m (Le about 150 to 35 pot ⁇ per linear incb) and -X-ostprdfC ⁇ br between 200and 400 / ⁇ m (about SO to 40 pore* pet linear inch.)
  • clastomcric matrices ⁇ iat are r ⁇ cd to .yjiic-stethoacafiGjld part of this invo ⁇ ti ⁇ o have sufficient resilience to allow substantial recovery, &g., to at least about 50% of the size of the'relaxcd confijgoratiott in at least one dimension, after being compressed foe ⁇ plantatioa in the human body, for example, a low compression set, e.g., at 25 0 C or 37 1 C, and sufficient stretigih and fl ⁇ flMfci ⁇ gh for the matrix to be used for controlled release of pha ⁇ aacniticaUy-active agents, such aj a drug * and for other medical applications.
  • chstot ⁇ cric matrices of the invention have sufficient res3icnwtoj ⁇ lk)wiecov( ⁇ toalleast ⁇ rt 9 ⁇ ?4ofthosi»of ⁇ c relaxed configursitiott in at least one dimension after bring compressed for implantation in the human body.
  • Ae porous reticulated polymeric nattrix that is used to fabricate the implants of this invention has spy suitable bulk density, also known as specific gravity, consistent tyfth its other properties.
  • the bulk density may be fiom about 0.0OS to about 0.15 gfcc (from about 0.31 t ⁇ ab ⁇ ut9.4lVft3),pref ⁇ IyitomAt ⁇
  • Ib/ft3 and most preferably from about 0.024 to about 0.104 g/cc (fiom about 1.5 to about 6.5 ⁇ bff ⁇ ).
  • incne ⁇ flbo ⁇ lniioifcth ⁇ porou* of this invention may have a tensile atrt ⁇ g ⁇ of from about 700 to sbon ⁇ $2,500 kg ⁇ (fi «n. about 1 to about 75 psi).
  • da&omeric matrix may have a tensile strength of from about 709 to about 21 t O0O kg ⁇ r ⁇ (ftom about 1 to about 30 psi).
  • SufScicat ultiinato tensile elongation Is also desirable.
  • reticulated dastomeric matrix £& ⁇ n ultimate tensile elongation of at least about 100% to at least about 500%.
  • reticulated elastomerio matrix that is ⁇ ejitej&ibjdffltt ⁇ the jH ⁇ lan-s of this ⁇ tve ⁇ tioalias - acon ⁇ «m>«sfceng ⁇ off ⁇ mabout700to ⁇ cwropresascn ⁇ trj ⁇ n, foanot-iereas-bodim- ⁇ eticid flom about 7,000 to abotit 210,000 I ⁇ g/i ⁇ i2 (from about 10 to -Aotit300i ⁇ S) -d 75%coii ⁇ »*s8-onst ⁇ rf ⁇ .
  • jfx iaothcr embcK ⁇ n ⁇ reticulated elastom ⁇ ric matrix that is used to fabricate the implants of thi* invention.
  • b ⁇ aco ⁇ p «sjicm 8ct, when ⁇ at ⁇ rcfified to50%ofit8thi(dt ⁇ e ⁇ In another efl ⁇ odiiJ- ⁇ ⁇ tairto ⁇ eitdKN ⁇ cpt.
  • elastomoric matrix hac a cca ⁇ ression sot ofaot more than about 10%, Ioaaotlier ctxtbodime ⁇ t, elastom ⁇ ric tratx ⁇ ; baj a corop ⁇ rcssion set of not more than about 5Yo.
  • structma] materials for the inventive porous elastomers arc synthetic polymers, especially, but not exclusively, dastoitwric polymers that are resistant to biological degradation, for example polycarbonate polyurcthaucs, polycthar polywethsaes, polycarbonate polysil ⁇ x-uws and the like.
  • Such elastomer* are geoa ⁇ % hydrophobic but, pw ⁇ ni-r ⁇ hydrophobic or somewhat hydrophilic. Io another einbodi ⁇ se ⁇ t. such elastomers may bo produced with surfaces that arc less hydrophobic or somewhat hydrophili ⁇
  • the invvnt-ou ⁇ ovides a biodurabl ⁇ da ⁇ tor ⁇ sric polyinenanc matrix which compri ⁇ ea a r ⁇ lycaibomtejHrfyol c ⁇ ir ⁇ oni ⁇ andm thpwby faa ⁇ tt poxes, followed by r ⁇ ticulatton of the foam to provide a biodarable rcticulatablo elastomeric product
  • Ihc prodiict is dcsigifflted ⁇ ipolyc ⁇ oiiatepotyi-reJ.i.m gjnv ⁇ s fo ⁇ aed from, eg, the isydroxyl
  • the -rfbvt ⁇ hydfophoWc polymeric autrix contains at least one polyol co ⁇ oneot Fort ⁇ M ⁇ ⁇ «r ⁇ os « of this application, i! ⁇ etQ ⁇ n * ⁇ olyol cox ⁇ oi ⁇ b ⁇ fc ⁇ ta molecule, Uu, & difiaictioaal polyol or a diol, as well as those ⁇ joleculcs cpmpriaing, on the average, groatcf than about 2 hj'droxyl grm ⁇ spwii»le «jl«,Le ⁇ apofyoI ⁇ ffaiayh ⁇ -ft ⁇ cti(?nal
  • polyol w ⁇ oncnt that is generally of a relatively low molecular weight, typically firom about I 1 OOO to about 6,000DaItOnS. Ibis, the ⁇ polyols are g ⁇ tt ⁇ ra ⁇ this soft segment polyol Is ter ⁇ anat ⁇ dwithhydtoxyl groups, nthcrpritttay or seco ⁇ d-try.
  • Bxajs ⁇ tes of sv ⁇ tabl ⁇ polyol corflpo ⁇ onts are polyether polyol, polyester polyol, polycaibo ⁇ at ⁇ polyol, bydroc ⁇ rbo ⁇ polyol, polysiloxa ⁇ e polyol, polyfcthcr-ttwster) polyol ⁇ oly( ⁇ thcr-co-carbo ⁇ at ⁇ ) polyol, polyCeth ⁇ r-co-hydrocarboi.) polyol, ⁇ oly(c-hcr-co--y'loxanc ⁇ polyol, poly(ester-co-carbon- «c) polyol, polyCester-coiydrcxjarbon) poiyol, polyCest ⁇ t-co ⁇ sioxw ⁇ ) polyol, poly((»rbonate ⁇ ydro « ⁇ rbo ⁇ ) polyol, poly(carbonBtc- ⁇ >o-siloxane) polyo
  • Polysiloxan ⁇ polyols with an average number of hydroxy! groups per molecule greater titan 2, ⁇ &, a polysiloxa ⁇ e triol can be made by using, for exatdple, methyl hydtoxy ⁇ usthyl siloxa ⁇ e, in the preparatioa of the polysiloxane polyol component
  • a particular type of polyol need not, of course, be limited to those formed from a single monwncric unit
  • a polyo& ⁇ r-typo polyol can be fbiroed fonn a nrature ⁇ rf ethylene oxide and propylene oxide.
  • copolymers or copolyofe caa be formed from any of the above p ⁇ lyote ty methods known to Qiose in the art.
  • the copolymer is s poly(ethw ⁇ M»rt ⁇ ai ⁇ te) polyol, po ⁇ Cc ⁇ er-co- hydr ⁇ boa)polyoUpoM ⁇ * « ' W ⁇ ox-U- ⁇ ) polyol, pol ⁇ poiy( ⁇ aiboii3 ⁇ e ⁇ o- ⁇ iloxaae)poIyo!
  • f po ⁇ y(hydrocaiiNM-c ⁇ Bi another embodjawnt, fee copolymer is a poly(cari>on-tte-c ⁇ 4 ⁇ ydrocaiboii) polyol, poly(c-i-tonat& ⁇ o-siloxflnc) polyol, polyO ⁇ diraaibon-eo-sfloxnne)pol ⁇
  • the copoiy ⁇ wtii a poly(carboaate ⁇ »*ydroc3ibon) polyoL
  • a poly(fi-ri ⁇ mal)e- « ⁇ >-hydrocart»n) polyol can be fc ⁇ ned by polyroeriang l.o ⁇ naianedjol, 1,4-tut-racdio! and a hydnwa ⁇ on-typ ⁇ polyol with carbonate.
  • the molecular wd ⁇ it of tfae polyol is varied, ta another et ⁇ xrii ⁇ Knt, the fkin ⁇
  • isocyanate component includes molecules composing, on the average, about 2 isocya ⁇ ate groups per molecule as well as those molecules comprising, on the average, greater than about 2 isocya ⁇ ate groups per molecule.
  • ts ⁇ cyanat ⁇ groups of the isocyanat ⁇ compo ⁇ ent $ ⁇ re*ctive with reactive hydrogen groups of the other ingredients e.g., with hydrogen bonded to oxygen in hy&oxyl groups and with hydrogen bonded to nitrogen in amine groups of the polyoi component, chain extender, crowlinker and/or water.
  • tit ⁇ avoiago number of iso ⁇ yaaat ⁇ jroups per molecule in the isocyanate component is about 2.
  • the average number of isocyanatc groups per molecule in ttte iso ⁇ ya ⁇ aie compottemt is greater ⁇ an about 2 is gftator than 2.
  • Exe ⁇ lary dilaocyanates include aliphatic diisocyanates, isocyanates corapriniog aro ⁇ wtio groups, &e so ⁇ cail ⁇ d "aromatic t- ⁇ iso ⁇ a ⁇ iIte8 ⁇ and ⁇ uresthen ⁇ AIii ⁇ Cdiisotf>T-nit «n-clu(tetetea-acthylcne ⁇ 3 ⁇ jtocyanate, cyclohcxa ⁇ -l ⁇ -diiKKyanat ⁇ , ⁇ lo ⁇ ie3ane'l,4-diisocyai-flle, hexamethyleac d ⁇ socyanatc, i30 ⁇ riboR»u ⁇ -jiso( ⁇ aflate, methyl
  • Aromatic d ⁇ socyanates include j ⁇ henyleaa d ⁇ sotyanafa ⁇ , 4,4'-dipbenyIn»thane d ⁇ socyanate (" ⁇ '-MDI”), 2,4'- ⁇ -pheityl ⁇ th-me d ⁇ swyaaaic ("2,4'-MDD, 2,44oltwne d ⁇ ajcya ⁇ at* (“2,4-TDI”), 2,640IuOOe diisocyaiiat ⁇ 'TDF), m-tetfamethyks'Iene dusocyacate, and mixtwos ⁇ w ⁇ of.
  • 2,4 f -MDI an ⁇ with 50to 95 %bywci ⁇ »tof4,4 ( Ai[DL Witfac ⁇ itbei ⁇ Wwidbya- ⁇ particul-irthcoiy.iti-; tliou ⁇ -t ft- ⁇ ⁇ e use ofhigher amounts of 2,4 ⁇ MDI-nables ⁇ 4 with4/t'-MDIr ⁇ s ⁇ ilts i ⁇ oftwcIa3tQincrio matrix because of die dis ⁇ iption of fifcte cryutaIMty of the hard segment arising out of thtj asymmetric 2,4'- MDI structure.
  • the starting material ⁇ fthe porous biodarablei ⁇ cul-aed daao ⁇ i ⁇ ric partially hydrophobic polymeric matrix contains suitable chain extcndexs prclcrabfyfor &e herd segments include diois, diamines, alfca ⁇ ol amines aod mixtures thereof M ⁇ ⁇ entbodir ⁇ t, the chain extender is an aliphatic diol having from 2 to iOcarljen atoms.
  • the ⁇ olrfiaioextrader is Mjectedfo ethylene glycol, ⁇ ,2* ⁇ r ⁇ pane dial, 13-propan ⁇ ⁇ ol, l ⁇ Miutane diol, 1 ⁇ -pent ⁇ c dioJ, diethylone glycol, ttt ⁇ thyleae glycol and n ⁇ ws thttt ⁇ i U ⁇ Mihw ⁇ otaftmont, tita ⁇ tek extender is a diamine having from 2 to 10 carbou atom*.
  • the diamine chain extender is selected ftom ethylene diamine, i,3-diaraintifautanc, 1,4-dia ⁇ iobutanc, 1-5 diaminopeatane, 1,6-diarrtmoho ⁇ a ⁇ e, 1 J-diammol-qpta ⁇ i ⁇ , U ⁇ - diaminooctaaa, iaophorono diamine andir ⁇ turcs t&ete ⁇ fc Ih a ⁇ otksr cmboiiiiti ⁇ it, the chain extender is an all»i ⁇ la ⁇ ii ⁇ ehi ⁇ gfrom2t ⁇ l ⁇ OTrbr ⁇ i ⁇ selected from di ⁇ thanolamioc, tricthanolan ⁇ w, isoptopa ⁇ olami-w, dntiethylefhaoolainine, m ⁇ thyldi ⁇ rtliaiiolam-
  • thermoplastic p ⁇ lyttrethaoe elastomers include p ⁇ -ycaibonaie polyurethanes, polyester p ⁇ lyurethaiies, potycthcr polyurethancs, polys ⁇ oxane polyurethfl ⁇ es, polyurethanes with so-called "mixed" soft segments, and mixtures thereof.
  • Mixed soft segment polyurethancs are known to those skilled in the art and include, e.g., polycarbonatt- ⁇ ofyester polyurethanes, polycaxbonate-polyether polyut ⁇ themes, polycarbDnat ⁇ po-yBiloxafle polyurethai.es, polyester- polyeifc ⁇ poty ⁇ ireihancs, polyester ⁇ ]h another e ⁇ tbodimeat, the fherautpht ⁇ c polyur ⁇ thafl* elastoraor comprises at Jwst one diisocynnat ⁇ In the isw:ya ⁇ aie ⁇ »mpoa ⁇ mt, -tf lc ⁇ combination of the d ⁇ s ⁇ cyanates, difimctionai chain extenders and dt ⁇ la described in detail above,
  • the weight average molecular wejgfrt of the thcmt ⁇ plastio elastomer is from about 30,000 to about 500,000 DaJto ⁇ s.
  • the weight average mol ⁇ cularwei ⁇ ttt of the the ⁇ noplastic elastomer is from about 50,000 to about 250,000 Balto ⁇ s,
  • thwiooplastic polyurctha ⁇ cs &r practicing Uic I ⁇ v ⁇ rtion in one embodiment suitably characterized as described hw ⁇ in, induclo: polyure&ancs witii mixed ioft segments co ⁇ ribi ⁇ gp ⁇ fysil ⁇ x& ⁇ togefl- ⁇ fwitfa »polyBthw*ad'orapolycarfjoiiat ⁇ c ⁇ one ⁇ t I ⁇ disclosed by M ⁇ etal. in U.S. Patent No. 6;m,254; and ⁇ osepolyiirethrae3 dfe ⁇ 01145,986,034.
  • Soi ⁇ »coinmercially ⁇ va-Iable ⁇ c ⁇ no ⁇ !9 ⁇ icela ⁇ include Ae line of polycarbonate polyure ⁇ a ⁇ s si ⁇ plied under the trodemaifc BIONATE® by The Polymer Technology Group lac, (B ⁇ isl ⁇ y, CA).
  • the reticulated elastomerie matrix tiat is used to ⁇ bricato the implant can be readily pwrocaWe to Jiqaids, pe ⁇ mttt ⁇ g flow of liquids, inctoding blood, through the composite device of tfa ⁇ invention.
  • the water pe ⁇ neability df the reticulated elastotn ⁇ ric matrix is from ab ⁇ rt25 l/ ⁇ ji ⁇ - ⁇ c ⁇ n2 t ⁇ ab ⁇ ut l ⁇ t ⁇ ]/n ⁇

Abstract

L'invention concerne un appareil endovasculaire auto-expansible pour occlusion d'anévrismes, ledit appareil comprenant un cadre déformable à mémoire de forme comprenant au moins un revêtement partiel de segment constitué d'un matériau d'implant matriciel. Le dispositif peut être plié et/ou étiré afin d'adopter un profil étroit pour être placé dans un dispositif de délivrance coaxial et s'étend en place en adoptant sa forme originelle lors de la libération du dispositif dans un anévrisme. L'invention concerne également un procédé de traitement d'un anévrisme, comprenant les étapes consistant à : (a) utiliser l'appareil endovasculaire auto-expansible inséré dans une lumière d'un dispositif de délivrance comprenant une terminaison proximale et une terminaison distale, la terminaison distale comprenant une extrémité distale ; (b) avancer l'extrémité distale du dispositif de délivrance dans une ouverture dans un anévrisme comportant une poche intérieure ; (c) avancer l'appareil au travers de la lumière dans l'ouverture ; et (d) retirer le dispositif de délivrance, l'appareil s'étendant dans la poche et recouvrant l'ouverture.
PCT/US2007/007320 2006-03-24 2007-03-23 Dispositif endovasculaire auto-expansible pour occlusion d'anévrismes WO2008051279A1 (fr)

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CA002647321A CA2647321A1 (fr) 2006-03-24 2007-03-23 Dispositif endovasculaire auto-expansible pour occlusion d'anevrismes
BRPI0709084-6A BRPI0709084A2 (pt) 2006-03-24 2007-03-23 dispositivo endovascular auto-expansìvel para oclusão de aneurisma
JP2009501592A JP2009530042A (ja) 2006-03-24 2007-03-23 動脈瘤閉塞用自己拡張型血管内デバイス
EP07835714A EP1998717A1 (fr) 2006-03-24 2007-03-23 Dispositif endovasculaire auto-expansible pour occlusion d'anévrismes
US12/294,210 US20090318941A1 (en) 2006-03-24 2007-03-23 Self-Expandable Endovascular Device For Aneurysm Occlusion
AU2007309715A AU2007309715A1 (en) 2006-03-24 2007-03-23 Self-expandable endovascular device for aneurysm occlusion

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US60/785,901 2006-03-24

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US20090318941A1 (en) 2009-12-24
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